Beruflich Dokumente
Kultur Dokumente
doi:10.1152/physrev.00015.2012
INTRODUCTION
GASTRIC ACID SECRETION
INTESTINAL CALCIUM ABSORPTION
REGULATION OF CALCIUM HOMEOSTASIS
THE STOMACH AND CALCIUM
CONCLUSIONS
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I. INTRODUCTION
The average adult human body contains 1.6% calcium,
which relates to 1,120 g in a 70-kg individual (743). Ninetynine percent of the calcium is stored in bone and teeth and
is therefore inaccessible to most physiological processes
(743). Although the amount of the immediately accessible
11 g (1%) of calcium may seem miniscule, this fraction
represents a pivotal constituent of our body. It serves a
broad diversity of roles, which range from intracellular signaling and maintenance of membrane integrity to muscle
contraction and neuronal transmission.
To allow for these calcium-dependent processes to function, our body undertakes extensive measures to keep the
intracellular and extracellular calcium concentrations and
the gradient between these two compartments stable. The
extracellular calcium concentration is typically clamped at
1.1 mM, whereas the intracellular environment is kept at
a 10,000 times lower concentration. In consequence, relatively small disturbances in calcium homeostasis can lead to
severe symptoms, such as cardiac arrhythmias or cognitive
dysfunctions. To maintain eucalcemia, our body is therefore tightly regulating the balance between calcium absorption by the intestine and calcium excretion by the kidney. In
addition, calcium is deposited in or extracted from bone,
which serves as a dynamic calcium reservoir. These three
organ systems, i.e., the intestine, the kidney, and bone, are
precisely controlled by a complex endocrine network,
which primarily consists of the calcitropic hormones: 1,25dihydroxyvitamin D [1,25(OH)2-vitamin D], parathyroid
hormone (PTH), and calcitonin.
This review mainly focuses on the question as to how calcium
enters the body through the intestine and how this mechanism
is regulated via the endocrine system. Furthermore, the process
of gastric acid secretion as related to calcium homeostasis will
be reviewed in detail. This may seem surprising, as gastric acid
secretion and intestinal calcium absorption are two distinct
physiological processes, which on first examination may not
seem to be interdependent. However, recent clinical studies
suggest that there may be a relationship between reduced gastric acid secretion and increased risk for sustaining bone fractures, which asks the question whether we need gastric acid to
absorb calcium efficiently through the intestine, or whether the
stomach exerts endocrine functions that impact bone health.
Indeed, it has been put forward several decades ago that gastric acid solubilizes calcium that is then complexed with other
dietary constituents, thereby allowing for a more efficient absorption in the intestine (18, 520, 699, 797). Furthermore, it is
long known that a partial or complete resection of the stomach
results in decreased bone density, also leading to fractures (58,
305, 732, 876). The stomach, the intestine, and bone are therefore functionally more intertwined than one may initially assume. This review will independently analyze the processes of
gastric acid secretion, intestinal calcium absorption, and their
respective neuroendocrine control and will conclude with a
critical attempt at illustrating where these two seemingly independent organ systems intersect in terms of calcium homeostasis and bone health.
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I.
II.
III.
IV.
V.
VI.
1. H-K-ATPase
The gastric H-K-ATPase belongs to the
family of P2-type ATPases, which also includes the ubiquitous Na-K-ATPase and the sarcoplasmic reticulum
Ca2-ATPase (SERCA). As the name implies, it exchanges
one intracellular hydrogen ion for one extracellular potassium ion at the expense of ATP. ATP is provided to the
pump by a large network of mitochondria, which occupy
up to 40% of the cell volume, making the parietal cell one of
the most mitochondria-rich cells in the body (292). In the
A) STRUCTURE.
Apical
Basolateral
PPIs
APAs
H+
SSTR
SST
H2
Hist
CCK2
Gast
M3
ACh
K+
cAMP
K+
KCNQ1
Kir
Ca2+
Cl
CFTR
CIC-2?
SLC26A9
Parietal cell
FIGURE 1. Parietal cell model. The gastric parietal cell is equipped with apical ion transport mechanisms that
allow for the secretion of concentrated hydrochloric acid. Activation of basolateral secretagogue receptors
mainly leads to an increase in either cAMP (histamine) or calcium (acetylcholine, gastrin), causing apical
insertion and activation of the H-K-ATPase. Somatostatin reduces intracellular cAMP levels. ACh, acetylcholine; APAs, acid pump antagonists; Gast, gastrin; Hist, histamine; PPIs, proton pump inhibitors; SST,
somatostatin.
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process of proton extrusion, the H-K-ATPase can overcome a massive acid gradient of 6 pH units, which is necessary to achieve sufficient gastric acidification. The pump
itself is a heterodimer, consisting of a subunit and a
subunit, while the individual pumps assemble as ()4 tetramers on the parietal cell surface (1). The subunit consists of 10 transmembrane domains and contains the catalytic site, which mediates ion exchange. The subunit stabilizes the subunit and is heavily glycosylated (41, 1105).
Mutational analysis of the glycosylated asparagine residues
suggests that these sites are critical for adequate membrane
delivery of the entire pump (41, 1105). Furthermore, the
subunit prevents a reversal of ion transport by a ratchetlike mechanism, which allows H-K-ATPase to pump
against the imposed high proton gradient (4, 294). Both
subunits share a significant degree of homology to Na-KATPase (697, 1012). This close relationship to other P2type ATPase has historically been exploited for homology
modeling of H-K-ATPase based on the crystal structure
of SERCA, which had been acquired in several conformational states (762, 815, 1092, 1093). Recently, however,
direct structural information on H-K-ATPase has been
obtained by electron crystallography, also in the presence of
the acid pump antagonist SCH28080 (2 4).
3. Potassium recycling
Even before the identification of H-K-ATPase, it has
been observed that potassium is necessary for acid secretion
to take place (335). To prevent the luminal depletion of
potassium, which would impair proton pumping by H-
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A) KCNQ1. KCNQ1 is a typical shaker-like six transmembrane spanning domain voltage-gated potassium channel
(1144). It was initially identified in the heart, where its
mutation can be responsible for cardiac arrhythmias
(1144). Yet, studies in KCNQ1 (/) animals revealed no
electrocardiographical abnormalities (641). Rather than
suffering from cardiac abnormalities, these animals surprisingly exhibited a distinct gastric phenotype with gastric hyperplasia, dilated gastric glands, vacuolated parietal cells,
hypochlorhydria, and hypergastrinemia (641). This observation led to the speculation that KCNQ1 may be the channel responsible for potassium recycling. Subsequently, immunohistochemical studies confirmed a colocalization of
the channel with H-K-ATPase, and acid secretion was
shown to be inhibited by pharmacological blockade (253,
391). Direct measurement of acid secretion in KCNQ1
(/) mice with modified Ussing chambers (pH stat) later
confirmed the initially observed hypochlorhydria (1029).
Interestingly, luminal substitution of potassium could rescue the acid secretory deficit, indicating that hypochlorhydria ensued from a true lack of apical potassium secretion
rather than a general morphological defect of the KCNQ1
(/) parietal cell (1029).
KCNQ1 is a peculiar channel in that it has a low conductance in acidic environments. In the context of the extreme
acidic milieu surrounding the parietal cell, this would impede its function as a potassium recycling pathway. To
circumvent this limitation, KCNQ1 attaches to a regulatory
subunit (KCNE2), which modulates the channels gating
properties and current amplitude (253, 391, 1087). Coassembly with KCNE2 activates KCNQ1 at acidic pH values
and thus facilitates the process of potassium secretion into
the gland lumen (391, 436). The importance of KCNE2 for
proper channel function is underlined by the observation
that KNCE2 (/) animals display a phenotype similar to
KCNQ1 (/) mice, i.e., hypochlorhydria, altered parietal
cell morphology, and hypergastrinemia (917).
B) KIR CHANNELS.
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Apart from being secreted through channels, potassium and chloride may exit the parietal cell through transporters. This alternative hypothesis is corroborated by a
recent observation of Fuji et al. (352). The group reported
that the K-2Cl cotransporter KCC4 coimmunoprecipitates
with H-K-ATPase in apical membrane fractions of parietal cells (352). Furthermore, flux measurements in H-KATPase containing vesicles showed decreased chloride and
proton transport under pharmacological blockade of
KCC4, suggesting a functional coupling of KCC4 to HK-ATPase (352). Although the hypothesis that both potassium and chloride leave the cell via a transporter is intriguing, the observation is, as of now, solitary and needs
further experimental validation.
Antrum
Basolateral
D-cell
Lumenal
Somatostatin
Basolateral
D-cell
VPAC
PACAP
VIP
CCK1
CCK
ENS
Somatostatin
Low
lumenal
pH
ECL-cell
SSTR
SST
G-cell
PAC1
PACAP
CCK2
Gast
SSTR
ENS
CaSR
CaSR
ENS
Histamine
Calcium
Amino acids
Polyamines
PPIs
APAs
SST
Gastrin
ACh
GRP
CaSR
H,K-ATPase
H2
Hist
Circulation
K+
CCK2
Gast
M3
ACh
ENS
SSTR
SST
Parietal cell
Somatostatin
D-cell
FIGURE 2. Neuroendocrine regulation of gastric acid secretion. In addition to direct neuronal regulation, the
parietal cell receives paracrine signals from neighboring ECL- and D-cells. Gastrin is produced in the antral
mucosa of the stomach and reaches the oxyntic mucosa via the circulation (endocrine regulation). Gastrinmediated histamine release represents one of the major stimulatory pathways leading to the secretion of
gastric acid (gastrin-histamine axis). The secretion of gastrin is closely tied to intragastric pH (via somatostatin), thereby creating a negative-feedback loop. ACh, acetylcholine; APAs, acid pump antagonists; ENS, enteric
nervous system; Gast, gastrin; Hist, histamine; PPIs, proton pump inhibitors; SST, somatostatin.
stimulation (313, 314). Apart from PKC and CaMKII activation, cholinergic signaling activates parietal cell MAPKs,
which is partially a downstream effect of PKC activation
(771, 1039, 1062, 1063). MAPK activation seems to have a
biphasic effect on acid secretion (acute inhibition and
chronic augmentation) and also serves as a mediator of
trophic responses in the parietal cell. For example, pro-
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H+
A) SYNTHESIS.
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The plasma levels of gastrin are closely tied to the intragastric pH. Low intraluminal pH is a potent inhibitor of gastrin
release, which serves as a negative-feedback mechanism to
impede an overproduction of acid. Conversely, a more alkali intragastric pH induces the secretion of gastrin, which
accounts for the commonly observed hypergastrinemia in
states of acid suppression, such as during proton pump
inhibitor (PPI) therapy. The pH dependency of serum gastrin levels is mainly relayed via somatostatin, as acid directly stimulates somatostatin release (see sect. IIB4). Somatostatin, released by neighboring antral D-cells, in turn acts
as the main inhibitor of gastrin secretion (FIGURE 2). The
physical proximity to G-cells allows for a fine paracrine
regulation of gastrin release. Although it is generally accepted that intragastric pH mostly modulates local somatostatin levels, the G-cell may also directly sense intragastric
pH via CaSR. CaSR is acid sensitive, and it has been shown
that isolated rat G-cells secrete less gastrin when the extracellular pH is dropped from 7.4 to 5.5 (569). However,
more investigations are needed to substantiate this evidence. Furthermore, gastrin release is also inhibited by neuronal regulation by the ENS. The neurotransmitter galanin
has been demonstrated to exert a direct inhibitory effect on
isolated G-cells (695, 961).
C) CELLULAR EFFECTS. Following secretion, gastrin enters the
bloodstream and acts on its target cells in an endocrine
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Histamine is the
effector of the gastrin-histamine axis and directly stimulates
the parietal cell to secrete hydrochloric acid (FIGURE 2).
Histamine is derived from the amino acid histidine, which is
enzymatically converted to histamine by L-histidine decarboxylase (HDC) (957). The effects of genetic HDC deletion
are predictably severe: animals lacking HDC have a low
basal acid output that does not respond to exogenous administration of gastrin (1066).
Histamine is stored in secretory granules of the ECL cell and
is released into the surrounding milieu in response to stimulation by gastrin and neuronal signals. Stimulation by gastrin occurs via activation of its GPCR CCK2 (772, 904).
Gastrin affects the ECL cell in multiple ways. First, gastrin
exposure increases the levels of HDC expression by enhancing its transcription and inhibiting its degradation, to allow
for increased synthesis of histamine (268, 331). The molecular mechanism underlying increased HDC transcription is
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fairly well understood. Following CCK2 activation, increased transcription of HDC is mediated via a PKC- and
ERK-dependent pathway (470, 472). The HDC gene promoter is then activated by at least three distinct nuclear
factors which bind to gastrin response elements, resulting in
gene transcription (889, 890). Apart from augmenting gene
transcription, gastrin regulates the degradation of HDC,
which further increases intracellular enzyme levels (331,
1214). Second, gastrin enhances the transcription of the vesicular monoamine transporter type 2 (VMAT2; SLC18A2),
which is responsible for accumulating histamine in the secretory vesicles (376). Similarly to HDC, this effect depends
on PKC and ERK activation and binding of a nuclear factor
to a gastrin response element in the VMAT2 promoter region (164, 1154). It should be mentioned that gastrin regulates the transcription of a plethora of other genes which
serve a diverse array of roles, ranging from growth to metabolism (346). Amongst many others these include chromogranin A, which is essential for granule packaging and is
a precursor of pancreastatin (see sect.VD3) (231). Third,
gastrin induces the fusion of secretory granules and the
release of histamine into the gland environment. Secretion
follows a biphasic elevation of intracellular calcium concentrations after activation of CCK2 (1201). The biphasic increase has been proposed to result from initial IP3-mediated
release from intracellular stores, which is followed by subsequent influx of calcium via L-type calcium channels from
the extracellular space (1201). The importance of intracellular store mobilization has been contested by a different
group, which proposed that solely influx trough L-type, and
to a lesser extent N-type, calcium channels triggers the secretory response (673). Lastly, gastrin has a trophic effect
on the ECL cell (see sect. IIB2).
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Somatostatin is the global antagonist of the acid secretagogues. It is produced by intestinal and gastric D-cells, the
latter of which exist in two populations in the stomach (61):
an antral population locally inhibits the release of gastrin
from G-cells, whereas a population localized to the acidproducing oxyntic mucosa directly regulates the parietal
cell and inhibits histamine release from the ECL cell (FIGURE 2) (19). The morphology of the D-cell is characteristic
in that it possesses long cytoplasmic processes, which allow
it to communicate with and regulate neighboring cells in a
paracrine fashion (620, 632). It is worthwhile to distinguish
the two populations of gastric D-cells, as each population
possesses unique physiological properties (1202).
The antral D-cell is mostly regulated by the local concentrations of gastrin, cholecystokinin, and intraluminal pH.
Gastrin induces somatostatin secretion from D-cells, which
causes reciprocal inhibition of gastrin release from neighboring G-cells, thereby creating a local negative-feedback
loop (976, 1011, 1202). The molecular mechanism underlying this loop is, however, less clear. CCK2 receptor is, if at
all, only expressed at very low levels in the antral mucosa
(749, 905, 967). It has been proposed that gastrin stimulates somatostatin release in the antrum in a receptor-independent mechanism (1202). This may be accomplished via
direct cell-cell contacts between the G- and the D-cell,
which have been demonstrated with electron microscopy
(620). Conversely, evidence for cholecystokinin and its
stimulatory role for somatostatin release via CCK1 is more
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B) CELLULAR EFFECTS.
It was recognized in the early 1950s that serotonin was present in the antral mucosa of dog stomachs
(323). Serotonin is stored in granules of enterochromaffin
cells of the antrum (1099). It is released into the circulation
and the gastric lumen in response to vagal stimulation (107,
649). Intraluminal acidification serves as another stimulus
for serotonin release (1196). Serotonin has an inhibitory
effect on the secretion of gastric acid (107, 153, 521, 650,
720, 903). It is still poorly understood where serotonin
interferes with acid secretion.
5. Other substances
D) NEUROTENSIN.
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C) SEROTONIN.
Neurotensin is a 13-amino acid neuropeptide that was originally isolated from calf hypothalamus
(161). In the periphery, it is also produced and secreted
postprandially by specialized endocrine cells (N-cells) of the
Neuropeptides of the gastric ENS that stimulate the secretion of somatostatin include PACAP and VIP, which both
bind to the VPAC receptor expressed on D-cells (199, 657,
1207). The presence of VIP and PACAP containing neurons, which integrate signals from the vagus nerve, has been
demonstrated in the gastric mucosa (302, 737). Furthermore, cholinergic signals can act on the antral D-cell via the
M3 receptor to promote secretion of somatostatin (140).
This is in sharp contrast to D-cells from the oxyntic mucosa
that are inhibited by cholinergic signals (197, 200, 1182).
As mentioned earlier, the D-cells in the oxyntic mucosa also
differ in their morphology. D-cells in the oxyntic mucosa
are of the closed type and have thus not been implicated to
participate in acid sensing. They exert their acid-suppressive effects by the paracrine regulation of ECL and parietal
cells. Further functional divergence between antrum and the
oxyntic mucosa has been demonstrated in the regulation of the
somatostatin mRNA. For example, suppression of acid secretion with omeprazole in fasted animals markedly decreased
somatostatin mRNA levels in the antrum, whereas the levels in
the oxyntic mucosa were affected to a much lesser extent,
which further corroborates the hypothesis that the antral cells
are involved in luminal chemosensation (945).
F) NITRIC OXIDE.
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2. H2 antagonists
The development of H2 blockers is inseparably intertwined
with Sir Blacks discovery of the H2 receptor on the gastric
parietal cell at the Smith Kline and French Laboratories
(now GlaxoSmithKline) (106). In his original publication,
Sir Black also describes burimamide as a competitive H2
antagonist that can effectively inhibit pentagastrin-stimulated gastric acid output in human volunteers (106). Further
development of the antagonist led to the synthesis of cimetidine, which was first commercially introduced in 1976 in
the United Kingdom, followed by the United States in 1977.
Other commonly used members of H2-antagonist family
now include ranitidine, famotidine, and nizatidine.
H2 antagonists prevent histamine-mediated stimulation of
the parietal cell by competitively interfering with its receptor. Although this effectively terminates the gastrin-histamine axis, the parietal cell is still susceptible to cholinergic
stimulation via the M3 receptor. This partial inhibition
mainly accounts for the lower clinical efficacy of H2 antagonists compared with PPIs, which directly target H-KATPase as the final target of all parietal cell stimuli (384).
For example, a meta-analysis concluded that patients
treated for bleeding peptic ulcers are about twice as likely to
suffer from persistent or recurrent bleeding if treated with
H2 antagonists compared with PPIs (384). Another metaanalysis also demonstrated a higher efficacy of PPIs in treating esophagitis (83% healing rate with PPIs compared with
52% with H2 antagonists)(567). Today, H2 antagonists are
largely superseded by PPIs due to their higher clinical efficacy. Furthermore, with the exception of famotidine, H2
antagonists are extensively metabolized in the liver by the
CYP-450 system, leading to substantial drug-drug interaction profile (for review, see Ref. 506).
3. Antacids
Antacids directly neutralize gastric acid allowing immediate
short-term control of heartburn. They exist in various salt
formulations, the most common of which are carbonate
salts, such as CaCO3, MgCO3, or NaHCO3. The use of
calcium carbonate as a dietary calcium supplement is dis-
The molecular identity of the apical calcium entry pathway was unclear for a long time. Early experiments in isolated duodenal
brush-border vesicles revealed that calcium uptake was passive, saturable, sensitive to ruthenium red, 1,25(OH)2-vitamin
D dependent, and functionally optimal at a pH of 7.5 (740).
This black box characterization suggested that a specific
carrier was responsible for calcium absorption and in retrospect already provided us with accurate key characteristics of the transient receptor potential vanilloid channel
type 6 (TRPV6), which was later established as the primary
apical calcium uptake channel (740). In subsequent attempts to further unravel the nature of the calcium uptake
mechanism, various voltage-gated L-type calcium channel
blockers were used (474, 717, 838). Although isolated duodenal cells accumulated less calcium following application
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Enterocyte
D
D
VDR
D
RXR VDR
Transcription
Ca2+
PMCA
Transcription
Ca2+
Ca2+
Na+
Ca2+
Calbindin-D 9k
NCX
TRPV6
D
FIGURE 3. Transcellular and paracellular calcium absorption in the intestine. The transcellular intestinal
absorption of calcium relies on apical calcium entry through TRPV6, intracellular calcium transport by calbindin-D9k, and basolateral calcium extrusion via either NCX or PMCA. 1,25(OH)2-vitamin D regulates most of
these ion transport proteins on a transcriptional level. 1,25(OH)2-vitamin D passes the plasma membrane of
the enterocyte and binds to its receptor (VDR), which then heterodimerizes with RXR to initiate transcription.
Evidence also suggests that 1,25(OH)2-vitamin D regulates the permeability of tight junctions, which gate the
paracellular absorption of calcium. D, 1,25(OH)2-vitamin D.
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Ca2+
205
206
As will be discussed in
more detail later, 1,25(OH)2-vitamin D is one of the key
hormonal regulators of systemic calcium homeostasis (see
sect. IVA). Increased levels of 1,25(OH)2-vitamin D lead to
enhanced intestinal calcium absorption. Shortly after cloning of TRPV6, it was recognized that the channel is positively regulated at the mRNA level by 1,25(OH)2-vitamin D
(614, 1030, 1109, 1110). The TRPV6 promoter has multiple binding sites for the 1,25(OH)2-vitamin D receptor
(VDR) and is thus directly sensitive to increases in
1,25(OH)2-vitamin D levels (736). Consequently, VDR-deficient animals display a marked decrease in TRPV6 mRNA
levels, whereas administration of 1,25(OH)2-vitamin D in
wild-type animals results in an increase in mRNA transcription (1030, 1109, 1110). In conjunction with the rapidly expanding characterization of the channel itself, these observations supported the dogma that TRPV6 is the essential player
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uptake through the paracellular pathway (76, 615). In conclusion, the generation of TRPV6 (/) animals has sustainably challenged our model of transcellular calcium absorption by questioning the relative importance of TRPV6
and by introducing new potential targets of 1,25(OH)2vitamin D regulation.
2. Calbindin-D 9k
The following section will address the question of what
happens to dietary calcium after it enters the enterocyte. It
should be considered that transcellular calcium uptake and
cytosolic calcium homeostasis are two contradicting requirements for the enterocyte. A prominent transcellular
flux of free calcium will inevitably interfere with housekeeping functions of the cell, such as intracellular signaling.
Furthermore, it has been calculated from in vivo data that if
calcium were to diffuse freely (simple diffusion) through the
cytosol, uptake rates would only be 1/70th of the actually
measured values (129). Simple diffusion would constitute a
bottleneck in the process of transcellular calcium absorption if cytosolic calcium concentrations should be kept low.
A partial solution to this problem was found as early
as 1966, when Wasserman et al. (1151) identified a
1,25(OH)2-vitamin D-inducible calcium binding protein in
the chick intestine. The authors observed that calcium radioisotopes traveled faster across a cellophane membrane if
suspended in intestinal homogenates from rachitic, i.e.,
1,25(OH)2-vitamin D deficient, chicks than if suspended in
the homogenates from rachitic animals treated with
1,25(OH)2-vitamin D (1151). This indicated that calcium
was bound to a protein in the enterocyte and that expression of this protein was controlled by 1,25(OH)2-vitamin D
(1151, 1152). Subsequently, the calcium binding protein
was further characterized (1073, 1149, 1152). Expression
levels were shown to be highest in the duodenum and to
gradually decrease in more distal segments, which correlated with the degree of calcium uptake that has been attributed to each intestinal segment respectively in prior
functional investigations (1073). The mammalian isoform,
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gation provides another explanation for the initially observed partial sensitivity of transcellular calcium uptake to
L-type calcium channel blockers. The voltage-gated calcium channel Cav1.3, a member of the L-type calcium channel family, was recently identified in the apical membranes
of the distal jejunum and proximal ileum (751). Previous
observations were emulated, as the investigators again demonstrated a decrease in calcium absorption following application of L-type calcium channel inhibitors in the corresponding segments (751). The authors argued that uptake
through Cav1.3 may have previously been misinterpreted as
paracellular calcium uptake (751). However, it should be
noted that the calcium uptake assay used in this report did
not discriminate between transcellular and paracellular calcium movement. Subsequently, it has been observed that
L-type inhibitor-sensitive calcium flux is linked to stimulation of glucose uptake through the glucose transporter type
2 (GLUT2) (692, 750). Cav1.3 may serve as an alternative
calcium entry pathway that is active in states of luminal
calcium abundance and that coregulates glucose absorption
(692, 750). Further investigations will be needed to determine the contribution of Cav1.3 to dietary calcium absorption.
209
B) THE NCX.
210
In addition, NCX is not subjected to regulation by 1,25(OH)2vitamin D, which further contributes to the ambiguity concerning its importance in the process of calcium absorption.
This has been observed very early, when exogenous administration of 1,25(OH)2-vitamin D to vitamin D-deficient
animals did not increase sodium-dependent calcium transport, while doubling transport through PMCA (382). Furthermore, it was recently shown that a calcium-depleted
diet decreases duodenal NCX1 mRNA levels (583).
Of note, two members of the potassium-dependent sodium
calcium exchanger (NCKX) family, namely, NCKX 3 and
4, were also identified in the small intestine (658, 687, 688).
However, further functional investigations will be needed
to clarify their role.
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nent is less pronounced in the jejunum and disappears completely in the ileum, indicating that transcellular calcium
absorption is restricted to the proximal segments of the
intestine, as discussed previously (825) [this has been contested more recently, when transcellular flux was also noted
in the ileum (46)]. Compared with the transcellular pathway, the paracellular route has not received much scientific
attention. It has been put forward that the rate of paracellular calcium absorption is constant across the length of the
intestine and is neither sensitive to 1,25(OH)2-vitamin D
nor a low-calcium diet (824, 825, 1224). However, provided that enough dietary calcium is available to saturate
the transcellular pathway, observations indicate that net
calcium absorption is highest in the ileum, which has been
attributed to the sojourn time, rather than alterations in
paracellular permeability (290, 710). In the rat, the chyme
spends some 74% of its transit time in the ileum, which
allows for a long exchange period between lumen and
plasma (290). The diffusion rate itself is fairly low and only
amounts to 2% of the rate if calcium were to diffuse freely
between intestinal lumen and plasma (290). This effect is a
consequence of the diffusion barrier that tight junctions,
which act as functional gating molecules of the paracellular
pathway, impose on calcium flux.
IV. REGULATION OF
CALCIUM HOMEOSTASIS
Eucalcemia is maintained by the concerted effort of vitamin
D, PTH, and, to a lesser extent, calcitonin. All three hormones can influence serum calcium concentrations by acting on the intestine, the kidney, or bone. 1,25(OH)2-vitamin D, the active vitamin D metabolite, primarily modulates the intestinal absorption of calcium and will therefore
be discussed in most detail (FIGURE 4). Apart from hormonal regulators that influence the absorption, excretion,
and deposition of calcium, our body needs a mechanism
that allows it to sense the current levels of plasma calcium.
This task is fulfilled by the CaSR. It oversees the precise
regulation of the calcitropic hormones.
A. Vitamin D
As discussed previously, vitamin D is one of the key regulators of calcium homeostasis. Our body has two sources
for vitamin D, namely, a dietary source (vitamin D23) and
an endogenous source that relies on ultraviolet (UV) light
catalyzed synthesis in the skin (vitamin D3) (FIGURE 5).
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1. Historical perspective
From a historical perspective, the identification of vitamin
D is closely intertwined with attempts to understand the
pathophysiology of rickets. Rickets is characterized by
childhood skeletal deformities resulting from inadequate
osteoid mineralization and calcification of cartilage due to
decreased serum calcium levels during development. The
adult form equivalent of rickets is termed osteomalacia.
With the onset of industrialization, rickets became a prevalent problem in the 18th, 19th, and the beginning of the
20th century. In fact, the disease was so widespread at the
beginning of the 20th century that an investigation conducted by the German pathologist Schmorl on 386 children,
who had died before the age of 4 years, concluded that 90%
of them had had rickets (968). Even in present times nutritional rickets still remains a major public health concern in
developing countries (303, 757, 809). The seminal observations that led to the identification of vitamin D were provided by Mellanby in 1919 (733). He observed that dog
pups who were fed a severely restricted diet consisting of
porridge or bread were consistently developing rickets
(733). Development of rickets could be averted if their diet
was supplemented with cod liver oil, which we now know
to contain a high concentration of vitamin D (733). Mellanby (733) concluded that rickets is a deficiency disease
which develops in consequence of the absence of some accessory food factor or factors. Vitamin A had been discovered shortly before, and it was subsequently speculated that
it may represent the factor promoting bone formation
(733). This hypothesis was later rebutted by American biochemist McCollum who concluded that a substance which
is distinct from fat-soluble [vitamin] A must be responsible
for preventing rickets (727). Furthermore, he stated that his
experiments demonstrate the existence of a fourth Vitamin [vitamin D] whose specific property [. . .] is to regulate
the metabolism of bones (727). In parallel to the unraveling of the dietary component of rickets, scientists were independently discovering the importance of sunlight for disease prevention. The Polish pediatrician Raczynski was most
likely the first to demonstrate evidence for this hypothesis experimentally (881). He kept one dog pup in the shade while a
littermate was kept in the sunlight. Both dogs were breastfed
by their mother. After 6 wk, the bones of the dog that was kept
in the shade contained 36% less calcium (881). These observations were followed up by the German pediatrician Huldschinsky, who healed rachitic children after exposing them
intermittently for 2 months to the UV rays generated by a
mercury vapor quartz lamp (504). Hess and Unger (447) rep-
The model of transcaltachia mainly relies on the observation that 1,25(OH)2-vitamin D can exert effects that are too
acute to be attributable to transcriptional events. For example, intestinal calcium absorption was increased in chicks
within 14 min of 1,25(OH)2-vitamin D exposure, an onset
which is too rapid as to be of a genomic nature (785). It
should be noted that rapid effects of 1,25(OH)2-vitamin D
have also been suggested to influence the paracellular pathway (see above). Undoubtedly a careful evaluation of the
route of calcium flux, i.e., transcellular versus paracellular,
is necessary. At least, isolated intestinal cells respond with
increased uptake of radiolabeled calcium to acute 1,25(OH)2vitamin D exposure (568). It has been postulated that apart
from the VDR, a membrane-bound 1,25(OH)2-vitamin D exposure receptor, the 1,25(OH)2-vitamin D-MARRS (membrane-associated, rapid response, steroid binding) protein, mediates the acute effects of 1,25(OH)2-vitamin D (568, 779,
785).
Parathyroid glands
Bone
PTH
Kidney
Intestine
eases renal
Increases
calcium absorption
Increases intestinal
calcium absorption
1,25(OH)2-D
FIGURE 4. Endocrine regulation of serum calcium levels. Calcium homeostasis is mainly regulated by PTH and
1,25(OH)2-vitamin D. Both hormones act at their respective target organs to increase serum calcium levels.
213
7-dehydrocholesterol
UV-B (290-315nm)
Intestinal uptake
Previtamin D
Isomerization
Vitamin D
Vitamin D
Vitamin D
DBP
DBP
Hepatocyte
1,25(OH)2-vitamin D
Vitamin D
Mitochondria:
CYP27A1
ER:
CYP2R1
25(OH)-vitamin D
25(OH)-vitamin D
DBP
Proximal tubule
Glomerular
filtration
25(OH)-vitamin D
PTH
25(OH)-vitamin D
DBP
Mitochondria:
CYP27B1
Megalin
Calcium
1,25(OH)2-vitamin D
Target organs
FIGURE 5. Vitamin D metabolism. Vitamin D can either be synthesized in the skin or absorbed from our diet.
It is then transported to the liver where it undergoes 25-hydroxylation by one of two hepatic enzymes (CYP27A1
or CYP2R1). During transport through the circulation, vitamin D is bound to a carrier protein (DBP). The
25(OH)-vitamin-D-DBP complex passes the glomerular filter and is scavenged from the primary urine by the
apical megalin receptor of the proximal tubule. Here, 25(OH)-vitamin D is converted to the active vitamin D
metabolite 1,25(OH)2-vitamin D. DBP, vitamin D binding protein.
component of yeast and fungal membranes, a different precursor substance had to exist in animal skin. Again, it was
Windaus and colleagues who identified 7-dehydrocholesterol
as the provitamin in porcine skin, which is converted to vitamin D3 (cholecalciferol) under irradiation (1165). After these
discoveries, industrially produced vitamin D has rapidly been
used in medical applications and as a food fortification. To-
214
215
iments demonstrated that this process has linear, nonsaturable, and passive kinetics, suggesting that no specific carrier mechanism for vitamin D is in place (484). These observations were later replicated in in vivo models (483).
Absorption is highest in the proximal and mid small intestine (484). Since vitamin D is fat soluble, its absorption
mechanism is similar to that of dietary lipids. In an aqueous
media, vitamin D aggregates in micelle-like structures
(735). Its absorption is aided by the secretion of bile acids,
which is underscored by the observation that patients suffering from cholestasis can present with vitamin D deficiency and develop bone disease, such as osteomalacia or
osteoporosis (245, 445, 563, 721, 894, 953, 1018, 1080).
Apart from bile salts, formation of mixed micelles containing monoglycerides and free fatty acids represents another
factor that aids in vitamin D absorption (884, 1082; contested by Ref. 483). These substances increase micelle size,
which promotes the solubilization of vitamin D, thereby
increasing uptake (884). Clinically, pancreatic insufficiency, causing an impairment of triglyceride breakdown
through insufficient lipase secretion, leads to decreased vitamin D absorption (1080, 1127). This is a particular problem in cystic fibrosis patients, who often develop pancreatic
and concomitant vitamin D insufficiencies (33, 230, 625,
678, 924).
216
(933, 1078). Higher expression in females was also confirmed in biopsy samples from human subjects (370). A
regulation via sex hormones may underlie this phenomenon, as injection of estradiol was shown to induce
CYP27A1 activity (933). Interestingly, seasonal variations
in expression were also observed, which may represent a
confounding factor for decreased 25(OH)-vitamin D levels
during the winter months (370).
It should be noted that CYP27A1 can also hydroxylate
vitamin D3 at other positions (402, 950). These include
positions 27 and 26; however, the ratio for 25-:27-:26hydroxylation has been estimated to be only 100:15:3,
which demonstrates that 25-hydroxylation of vitamin D3 is
the most essential reaction catalyzed by the enzyme (950).
More importantly, CYP27A1 can also use its own product
25(OH)-vitamin D as a substrate to further act as a 1hydroxylase and produce the hormonally active form of
vitamin D, namely, 1,25(OH)2-vitamin D (50, 51, 950). As
will be discussed later, this reaction is normally catalyzed in
the kidney by another CYP family member (CYP27B1). At
the moment, it is not clear what the physiological significance of 1-hydroxylation by CYP27A1 is.
Mutations in CYP27A1 cause the autosomal recessive disorder cerebrotendinous xanthomatosis (CTX; OMIM
213700). The disease was first described in 1937 and is
characterized by cholestanol deposits that are most prominent in tendons, especially the Achilles tendon, the brain,
and the lung. Patients present with progressive neurologic
defects, atherosclerosis, and cataracts and commonly suffer
from diarrhea. The inadequate bile acid synthesis was first
noted in 1974 by Setoguchi et al. (993). Shortly after the
cDNA of CYP27A1 was cloned, it was demonstrated that
mutations of this enzyme were responsible for CTX (148).
In agreement with the dual role of CYP27A1, CTX patients
also suffer from osteoporosis, low 25(OH)-vitamin D levels, and impaired intestinal calcium absorption (83, 320).
Three CYP27A1 mutations that are known to cause CTX
and still lead to protein expression were recreated in vitro,
and enzymatic activity was assayed. Depending on the expression system, these mutants showed lower or higher 25hydroxylation activity than the wt enzyme, which led the
authors to questions the enzymes role in vitamin D metabolism (403). It should be considered that 1) many more
(38) mutations underlying CTX exist, 2) by far not all
patients exhibit disturbances in bone or vitamin D homeostasis, and 3) the investigated mutant enzymes may only
cause disturbances in cholesterol, rather than vitamin D
metabolism (83, 320, 403). In the light of these limitations,
it should be questioned whether CTX represents an apt
model system to evaluate CYP27A1 in the context of vitamin D metabolism.
With the introduction of novel genetic tools, a cyp27a1
(/) mouse was created in 1998 (918). However, the phe-
217
218
219
220
B) NONGENOMIC EFFECTS.
B. PTH
2. PTH1R
PTH exerts its physiological effects via activation of a membrane-bound GPCR, the parathyroid hormone receptor
type 1 (PTH1R) (PTH2R is mostly expressed in the CNS
and tissues that are not involved in calcium handling and
will thus not be reviewed). Of note, PTH1R is not exclusively located at the plasma membrane but can also localize
to the cell nucleus. The physiological significance of nuclear
PTH1R is currently unclear but may represent a novel signaling paradigm for the actions of PTH (830, 856, 857,
1155).
Full-length PTH is not required to activate PTH1R. The
NH2-terminal domain of PTH mediates most of the physiological effects of the hormone and is responsible for binding in the -- binding fold of PTH1R (861). This is why
clinically PTH(134) is used as a PTH analog with identical
biological activity (753, 867, 919, 1094). Conversely, NH2terminal truncation of PTH(134) to PTH(234) changes
the characteristics to a partial receptor agonist, whereas
further truncation to PTH(334) results in loss of biological
activity (1094).
PTH1R was first cloned from opossum in 1991, which was
followed by identification of the highly homologous human
cDNA shortly thereafter (536, 964). In the nonactivated
state the receptor is expressed as a homodimer at the cell
surface, which dissociates upon PTH binding (860).
PTH1R is a member of the class B (class 2, secretin family)
GPCRs. As many other GPCRs, it undergoes N-linked glycosylation at four asparagine residues (1218). Mutational
analysis revealed that site-specific mutation of all four sites
decreases cell surface expression, whereas impairment of
fewer glycosylation sites does not seem to have significant
effects on trafficking or ligand binding (1218). Furthermore, the extracellular domain of the receptor includes a
characteristic disulfide bond pattern involving six cysteine
residues (392). These residues are thought to be essential for
stabilizing the hydrophobic -- binding pocket for
PTH, which is conserved among all members of class B
221
secretion is extremely tight, given the bodys need to maintain the calcium concentration within a narrow window
(1.11.3 mM). Small alterations in calcium homeostasis can
have deleterious effects, for example, on the excitability of
neurons and muscles. The low plasma half-life of PTH of 5
min allows for a precise regulation of this balance (95). To
achieve controlled and rapid on-demand secretion of PTH, the
parathyroid is equipped with an ultrasensitive extracellular
CaSR, which constantly monitors the plasma calcium levels
and triggers intracellular signaling events and PTH release
upon imminent drops in calcium levels (FIGURE 6) (see sect.
IVD). PTH is further regulated on a transcriptional level by
1,25(OH)2-vitamin D, creating a negative-feedback loop
(154, 930, 931).
Calcium
Ca
PLC
Gq
PIP2
DAG
Kinase phosphorylation
Inhibition of
cell growth
IP3
Calcium
1,25(OH)2-D D
PLA2
ER
D
VDR
AA
Increases VDR expression
Nucleus
Inhibits PTH
secretion
Reduces PTH
synthesis
Parathyroid gland
PTH
FIGURE 6. CaSR signaling in the parathyroid gland. Increased serum calcium levels lead to an inhibition of
PTH secretion. Serum calcium levels are measured by the CaSR receptor. Activation of CaSR causes
generation of arachidonic acid (AA) metabolites, which inhibit the release of PTH and increase the expression
of VDR, thereby increasing the cells sensitivity to the negative feedback exerted by 1,25(OH)2-vitamin D.
1,25(OH)2-vitamin D suppresses the synthesis of PTH. Furthermore, CaSR activation inhibits parathyroid gland
growth.
222
example, knockout of -arrestin causes increased and sustained levels of the second messenger cAMP in primary
osteoblast cultures upon PTH stimulation (327). PTH1R
also associates with the scaffolding protein NHERF1,
which stabilizes the receptor at the cell membrane and prevents its endocytosis and desensitization (1022, 1139). This
effect of NHERF1 is partially attributable to a prevention of
an interaction between -arrestin and PTH1R (1140). Colocalization of NHERF1, -arrestin, and PTH1R has been
demonstrated and suggests that NHERF1 is constitutively
bound, whereas -arrestin association is more dependent
on receptor activation (580). Interestingly, it has recently
become apparent that -arrestin not only plays a role in
receptor desensitization, but also mediates activation of
downstream signaling cascades, such as MAPKs, in a G
D
RXR VDR
3. Cellular effects
PTH exerts its effects in two primary target tissues: bone
and the kidney.
In the kidney, PTH causes phostphaturia, increases calcium
absorption, and induces the synthesis of 1,25(OH)2-vitamin D. In-detail analysis of renal phosphate handling is
beyond the scope of this review and has been summarized
previously (334, 765). In brief, phosphaturia mainly results
from downregulation of the Na-Pi transporter type IIa
(NaPi-IIa) at the apical membrane of the proximal tubule,
thereby reducing the amount of reabsorbed phosphate from
the primary urine. Rather than directly modulating the
transporters activity, PTH exposure mainly affects the
number of active cotransporters on the plasma membrane.
Activation of basolateral PTH1R causes retrieval of NaPiIIa and targets it for lysosomal degradation, resulting in
diminished Pi reuptake (566, 682, 847). Apart from NaPiIIa, at least two other apical phosphate transporters are
present in the proximal tubule: NaPi-IIc and PiT-2 (986,
1124). Currently, there is some evidence that PTH can also
regulate NaPi-IIc and PiT-2, but additional studies remain
to be conducted (855, 987). Although a contribution of
these transporters to renal phosphate reabsorption is highly
likely, knockout studies suggest that NaPi-IIa is responsible
for 80% of total phosphate transport, thus representing
the major uptake mechanism (72, 468).
It has been recognized for over 30 years that PTH can
stimulate the synthesis of the active vitamin D metabolite
1,25(OH)2-vitamin D in the kidney (116, 338) (see sect.
IVA4). 1,25(OH)2-vitamin D in consequence enhances the
223
intestinal and renal uptake of calcium in an effort to counteract hypocalcemia, which initially led to secretion of PTH.
The PTH-stimulated increase in 1,25(OH)2-vitamin D levels is achieved on a transcriptional level. PTH upregulates
the transcription of CYP27B1, the mitochondrial enzyme
which is responsible for the conversion from 25(OH)-vitamin D to 1,25(OH)2-vitamin D. Transcriptional upregulation occurs via PTH binding to PTH1R, leading to increases
in the second messenger cAMP and activation of PKA (125,
442, 763, 764, 921).
Chronic
PTH
PTH1R
OPG
RANKL
Osteoblast
proliferation
RANK
Osteoclast
differentiation
H+
Osteoblast
Osteoclast
V-ATPase
FIGURE 7. The effects of PTH on bone. PTH has a dual effect on bone. Intermittent PTH exposure causes
osteoblast proliferation, leading to an increase in bone mass. Continuous PTH exposure results in RANKL
upregulation and concomitant OPG suppression (OPG serves as a decoy receptor for RANKL and prevents its
interaction with osteoclast RANK). The stimulated RANKL-RANK interaction leads to osteoclast proliferation
and increased bone turnover.
224
4. PTH fragments
It should be noted that full-length PTH(1 84) is not the
only circulating form of the hormone in the body. Various
PTH fragments can be found in the circulation, which partially originate directly from the parathyroid gland and partially represent products of peripheral cleavage. The parathyroid itself releases COOH- and NH2-terminal hormone
fragments, which are generated by cysteine proteases (cathepsin B and H) in distinct secretory vesicles of the gland
(418, 427, 693). Interestingly, the fraction of secreted hormone fragments changes with extracellular calcium conditions. It has been reported that more fragments are released
under conditions of hypercalcemia, when secretion of fulllength PTH is suppressed (417, 418, 605, 726). Peripheral
proteolysis represents the second source of PTH fragments.
This process occurs predominantly in liver and the kidney
(127, 234, 989). The group of fragments that have received
the most amount of scientific attention is the large NH2terminally truncated non-PTH(1 84) fragments. PTH(7
84) is the quantitatively major member of this group, which
is secreted by the parathyroids (233). The group of nonPTH(1 84) fragments can represent up to 20% of circulating PTH, but can increase in patients with renal failure
dramatically to up to 50% because of impaired renal clearance (130, 131, 444, 648). This is of particular interest, as it
has become recently apparent that the non-PTH(1 84)
fragments exert biological activity. In general, non-PTH(1
84) fragments antagonize the effects of PTH in its primary
target tissues, bone and the kidney but also the parathyroid
gland directly. It has been shown that PTH(7 84) can inhibit PTH release from the parathyroid, presumably in an
autocrine fashion, despite low serum calcium concentra-
Continuous PTH exposure, on the other hand, mainly affects osteoclast numbers and activation, thereby increasing
bone turnover. Since osteoclasts are canonically thought to
not express PTH1R (although this view has recently been
challenged, Ref. 260), the catabolic effects of PTH are relayed through osteoblast signaling. The PTH-induced
crosstalk between osteoblasts and osteoclast is mainly mediated by receptor activator of nuclear factor B (RANK),
osteoprotegrin (OPG), and RANK ligand (RANKL). Both
RANKL and OPG are expressed by osteoblasts and exert
opposing actions on osteoclasts. RANKL promotes osteoclastogenesis by binding to RANK on osteoclasts. Conversely, OPG serves as a soluble decoy receptor for RANKL
and thus inhibits its interaction with RANK, thereby suppressing osteoclastogenesis. In accordance with this model,
RANKL-deficient animals develop osteopetrosis because of
insufficient osteoclasts activation (592). Sustained PTH exposure affects RANK-RANKL signaling by downregulating antiresorptive OPG, while simultaneously stimulating production of RANKL by osteoblasts (FIGURE 7)
(350, 497, 679, 689). The enhanced RANK-RANKL signaling induces formation of osteoclasts, which in turn
leads to enhanced bone resorption and elevates serum
calcium levels.
C. Calcitonin
Calcitonin is a peptide hormone that has been discovered by
Copp et al. in 1962 as a factor that reduces serum calcium
concentrations (160, 227). Calcitonin production was initially falsely ascribed to the parathyroid glands, and it was
only later that the thyroid gland had been established as the
source of calcitonin (463). The primary sites of calcitonin
production are the parafollicular cells (C-cells) of the thyroid gland. Calcitonin exerts its hypocalcemic effects primarily by inhibition of osteoclast activity. It should be
noted that the importance of calcitonin in day-to-day calcium homeostasis in humans is rather negligible (see sect.
IVC4). For this reason, it will only be reviewed concisely.
225
In conclusion, non-PTH(1 84) fragments act as PTH antagonists and are secreted by the parathyroid in response to
hypercalcemia.
It has also been speculated that calcitonin may act directly on the collecting duct in a similar fashion to antidiuretic hormone (ADH or vasopressin), i.e., to concentrate the urine by increasing the reabsorption of water
from the primary urine (251). Indeed, calcitonin was
shown to increase the apical expression of aquaporin 2
(AQP2) in principal cells of the collecting duct (119).
Apical insertion of AQP2 and subsequent transepithelial
water movement is the primary mechanism by which
ADH causes concentration of the urine to lower plasma
osmolarity.
In conclusion, the direct impact of calcitonin on renal
calcium handling is quite vague and may be of minor
importance. However, calcitonin also has another, indirect effect on calcium homeostasis. Calcitonin was
shown to be an important regulator of the expression of
CYP27B1, the renal enzyme responsible for the conversion of 25(OH)-vitamin D to 1,25(OH)2-vitamin D
(1009, 1217). In normocalcemic rats, CYP27B1 mRNA
levels were inducible by calcitonin administration, leading to an increase in the production of 1,25(OH)2-vitamin D (1009, 1217). Furthermore, CYP24A1 was in-
226
D. The CaSR
The CaSR is a G protein-coupled membrane-bound receptor that is the primary sensor for calcium and is the first link
in the regulatory chain of calcium homeostasis. By regulating the release of PTH from the parathyroid to modulate
227
Calcium-sensing receptor
Kidney
Proximal tubule
Collecting duct
CaSR
CaSR
CaSR
HPO42
CaSR
CaSR
NaPi-IIa
Na+
H+
Ca2+
V-ATPase
TRPV5
25(OH)-vitamin D
CaSR
CaSR
Mitochondria:
CYP27B1
H2O
1,25(OH)2-vitamin D
AQP2
Enterocyte
ROMK
K+
CaSR
CaSR
NKCC2
CaSR
Na+
CFTR
2Cl
Cl
K+
3
Ca2+
H2O
Stomach
Bone
G-cell
PPIs
APAs
CaSR
CaSR
H+
H,K-ATPase
CaSR
CaSR
K+
?
Gastrin
CaSR
ECL-cell +
parietal cell
activation
Differentiation
and function
RANKL
RANK
?
Osteoblast
Circulation
H+
V-ATPase
Parietal cell
FIGURE 8. CaSR in the gastrointestinal tract, kidney, and bone. Kidney: the effects of CaSR activation on ion
transport in various nephron segments are shown. In the proximal tubule, CaSR stimulates phosphate
absorption and 1,25(OH)2-vitamin D synthesis. In the thick ascending limb of the loop of Henle, CaSR inhibits
apical potassium channels (ROMK), thereby inhibiting NKCC2 (potassium recycling). The resulting changes in
the lumen-positive potential inhibit paracellular calcium uptake. In the distal convoluted tubule, CaSR presumably stimulates apical calcium entry through TRPV5. In the collecting duct, CaSR stimulates proton extrusion
through the V-type ATPase and inhibits urine concentration through AQP2. Stomach: in the parietal cell, CaSR
induces acid secretion by activating H-K-ATPase. In the G-cell, CaSR activation results in gastrin secretion.
Of note, CaSR serves as a luminal nutrient and calcium sensor on the G-cell. Bone: CaSR on osteoblasts
presumably regulates their differentiation and RANKL expression. Intestine: in the intestine, CaSR activation
reduces water secretion by inhibiting chloride secretion through CFTR.
228
Osteoclast
Intestine
Thick ascending limb of
the loop of Henle
229
Once stimulated, the CaSR activates a variety of intracellular signaling cascades. Being a GPCR, most of these processes are mediated by G proteins. Specifically, Gq/11, Gi,
and G12/13 have been shown to be coupled to the CaSR
(40, 175, 495, 849). The expression of all subunits was
confirmed in bovine parathyroid (1115). Gi mediates the
suppression of cAMP levels by inhibiting adenylyl cyclase
and activates the ERK/MAPK pathway (175, 250, 375,
572). Activation of Gq/11 results in increased intracellular
calcium concentrations via activation of PLC and IP3 triggered calcium release (133, 1010). As demonstrated in HEK
cells, this cascade can also activate further downstream
phospholipase A2 leading to production of arachidonic acid
metabolites (415). G12/13 is thought to regulate phospholipase D and phosphatidylinositol 4-kinase (PI 4-K); however, this interaction has only been demonstrated in heterologous cell culture system (494, 495).
was shown that increases in calcium can potentiate the inhibitory effects of 1,25(OH)2-vitamin D (930). This effect is
most likely mediated by CaSR, whose activation can decrease
PTH transcription by augmenting the inhibitory effects of
1,25(OH)2-vitamin D. Molecularly this is achieved by upregulating the expression of the VDR (151, 162, 362, 653, 916).
The current working model states that activation of CaSR
causes an increase of arachidonic acid metabolites and activation of the MAPK pathway, which in turn results in increased
VDR mRNA levels (FIGURE 6) (151). This allows the parathyroid to adjust its 1,25(OH)2-vitamin D sensitivity to the current plasma calcium levels.
230
potassium (ROMK; Kir1.1) channel, mainly through arachidonic acid metabolites created by PLA2 (1147, 1148).
Apical ROMK releases potassium ions into the lumen,
which in turn are needed to fuel apical ion uptake through
the Na-K-2Cl (NKCC2) cotransporter. By decreasing
apical potassium efflux, CaSR inhibits sodium and chloride
uptake through NKCC2 (906). This correlation is reflected
in much earlier observations, which report that calcium
infusions can decrease tubular sodium clearance (300, 718,
1052). In addition, impairment of NKCC2 has also implications for calcium absorption. Reduced NKCC2 activity
decreases the lumen-positive potential and negatively affects countercurrent multiplication, and in consequence the
nephrons ability to concentrate urine (434). Both mechanisms will lead to impaired calcium absorption (434). Calcium absorption in the medullary portion of the thick ascending limb is thought to occur predominantly as passive
uptake through the paracellular route (995). Similar observations have been made when blocking NKCC2 pharmacologically with the loop diuretic furosemide (299). It has thus
been proposed that activation of basolateral CaSR has
loop diuretic-like effects, reducing NaCl but also calcium
absorption in the kidney (434).
5. CaSR in bone
It is well established that CaSR is expressed in osteoblasts,
osteoclasts, and their respective precursors (172, 174, 542,
11831185, 1192). The functional role of CaSR in these
cells is, however, less clear. Undoubtedly, both cell lines are
exposed to local fluctuations in calcium concentrations
making an adaptive response to the calcium environment
plausible. Indeed, changes in extracellular calcium concentration have been shown to regulate various cell functions,
mostly in in vitro models. Extracellular calcium can stimulate the proliferation, migration, and differentiation of osteoblasts (174, 297, 1183, 1184, 1186). Similarly, calcium
was proposed as a differentiation signal for osteoclasts
(542, 544, 734). Significant doubt about the in vivo importance of CaSR in bone has emerged with the generation of
the CaSR (/) mice. Although CaSR knockout results in
rickets, these animals suffer from severe hyperparathyroidism, which did not allow a discrimination between the effects of high PTH and CaSR on bone turnover (365). Con-
231
232
Back in the field of PPIs, the seminal epidemiologic investigation by Yang et al. was subsequently followed up by a
number of studies, which also focused on other types of
fractures, other populations, and other drugs reducing gastric acid output, such as H2 receptor antagonists (202, 228,
252, 394, 400, 559, 868, 923). Although their conclusions
were somewhat controversial, a recent meta-analysis supports the initial hypothesis that a correlation between PPI
intake and fracture risk (hip, spine, and any-site fractures)
exists (1195). The meta-analysis considered 11 studies and
identified an overall odds ratio of 1.30 for all fracture types
combined (1195). There was no association between H2
blocker intake and an increase in fracture risk, although
some single studies supported a link (228, 1195). Another
meta-analysis came to a comparable conclusion with regard
to an increased fracture risk under PPI exposure (616).
Proton pump inhibitors (PPIs, see sect. IIC1) are in widespread use for the treatment of acid-related disorders, such
as gastroesophageal reflux disease (GERD) or gastric ulcer
disease. They exert their curative effects by inhibiting the
acid output of the stomach. Over the recent years, mostly
epidemiological evidence has accumulated which links the
intake of PPIs to an increased risk of sustaining fractures,
especially in the elderly population. Yang et al. (1190) published one of the earliest and largest studies investigating
this potential correlation in 2006. Examining a population
of over 13,000 hip fracture cases and over 135,000 controls
over the age of 50, the authors concluded that long-term
(over 1 year) PPI use was associated with an increase in hip
fractures (AOR 1.44) (1190). Although the likelihood of
sustaining a fracture following PPI intake may seem fairly
low, the implications for public health are substantial. This
has multiple reasons: PPIs represent the third most commonly prescribed medication in the United States and are
also available as over-the-counter formulations. Furthermore, there is an ongoing debate whether PPIs are overprescribed, putting certain populations at unnecessary risk of
side effects. In combination with the high incidence of osteoporotic fractures, the mean incidence of hip fractures
alone between 1986 and 2005 was 957 per 100,000 women
over the age of 65 per year, a small increase in risk suddenly
has implications for a very large population (123).
233
234
C. Calcium Salts
Many investigators have employed calcium salts to determine the efficacy of intestinal calcium absorption. Furthermore, calcium salts are in wide clinical use as a dietary supplement. As will be discussed in this section,
calcium salts differ in their bioavailability, which not
only represents a potential source of error in experimental designs, but more importantly, has extensive clinical
implications.
235
1. Ghrelin
Ghrelin has been discovered fairly recently (1999) by Kojima and colleagues and is mainly implicated in regulating
food intake in the hypothalamus (588, 777). Ghrelin levels
are inversely correlated with body mass and elevated in
conditions of fasting, such as anorexia nervosa (377). Ghrelin is mainly synthesized and secreted in a pulsatile manner
by special neuroendocrine cells (P/D1 cells) in the fundic
region of the stomach (242, 777). The influence of ghrelin
on gastric acid secretion is discussed in a separate section
(see section IIB5E). A few years after its discovery, it was
shown that ghrelin can also directly affect osteoblasts (254,
357, 576, 691). Ghrelin induces osteoblast proliferation
and differentiation and inhibits their apoptosis (357, 576,
691, 1141). It is not entirely clear whether this effect is
mediated via the ghrelin surface receptor, the growth hormone secretagogue receptor 1a (GHS-R1a), or not. While
the receptor is expressed in rat and murine osteoblasts and
its pharmacological inhibition abolishes the effects of ghrelin on differentiation and proliferation, no GHS-R1a
mRNA could be detected in a human osteoblast cell line
(254, 357, 691). It should be noted that this effect is independent of growth hormone (GH). Ghrelin serves as a potent stimulator of GH secretion from the pituitary gland,
which in turn acts as an activator of osteoblasts through the
GH/IGF-I axis. However, the observations that 1) pharmacological inhibition of GHS-R1a attenuates the effects of
ghrelin and that 2) GH-deficient rats are still sensitive to
ghrelin, suggest a direct effect on osteoblasts (357). In vivo,
the activation of osteoblasts translates to an increase in
236
Several studies aimed to identify a link between serum ghrelin levels and BMD in human populations. The most recent,
and one of the largest (n 707 subjects), investigation
assessed BMD with peripheral quantitative computed tomography (pQCT). This technique allows for separate
analysis of trabecular and cortical bone. The results showed
a positive correlation between ghrelin and trabecular BMD
in elderly men and women (775). A different large-scale
study, investigating a similar cohort (n 977) found no
association using dual-energy X-ray and single-photon absorptiometry (1157). These techniques, however, do not
permit a discrimination between cortical and trabecular
bone. Other small-scale studies also came to contradictory
conclusions (388, 811). The reason for these discrepancies
is elusive. Since the formation of trabecular bone represents
a more dynamic process, its direct measurement may be
more sensitive to subtle changes than overall bone density
measurement (775). Baseline plasma ghrelin levels were
also shown to be inversely correlated to type 1 collagen
C-telopeptide (CTX), a marker for bone resorption (501).
The source of ghrelin represents another potential caveat. In
vitro studies suggest that osteoblasts can also synthesize
ghrelin (254, 357). Ghrelin was identified on the mRNA
and protein level by two investigations (254, 357). A different group did not find evidence for ghrelin in osteoblasts
(214). This has important implications, as ghrelin may be
secreted in an auto-/paracrine fashion, which would make
plasma ghrelin levels less significant for osteoblast activation. On the other hand, (partial) gastrectomy significantly
decreases plasma ghrelin concentrations, which could contribute to postgastrectomy osteopenia, although these may
just be two independent factors. Total gastrectomy causes a
drop in plasma ghrelin levels by as much as 70% (528).
Partial gastrectomy also severely decreases plasma ghrelin;
however, levels normalize depending on the type of resection to 48 88% of the preoperative levels due to compensatory production in the remaining gastric mucosa (528).
This recovery already occurs after 7days. It thus remains to
be elucidated if the slightly decreased ghrelin levels after
small gastric resections can account for the long-term phenomenon of postgastrectomy osteopenia. Furthermore, in
mice, the reduction of bone mass after gastrectomy cannot
be rescued by exogenous administration of ghrelin (277).
Ghrelin administration did also not affect markers of bone
resorption in gastrectomized patients, although these parameters were only measured very acutely 4 h after ghrelin
infusion (501). So far, no data on the effect of chronic
ghrelin treatment on BMD are available.
Acid suppression
Calcium solubility
Gastrin
Intestinal absorption
Pancreastatin
Calcitonin
PTH
FIGURE 9. Model summarizing the potential impact of acid suppression on calcium homeostasis.
237
ACKNOWLEDGMENTS
S. Kopic is a Howard Hughes Medical Institute International Student Research Fellow. Special thanks to Sashka
Dimitrievska for her untiring support and critical editing of
the manuscript.
Address for reprint requests and other correspondence: J. P.
Geibel, Yale School of Medicine, 310 Cedar St., BML 238,
New Haven, CT 06510 (e-mail: John.geibel@yale.edu).
REFERENCES
1. Abe K, Kaya S, Taniguchi K, Hayashi Y, Imagawa T, Kikumoto M, Oiwa K, Sakaguchi
K. Evidence for a relationship between activity and the tetraprotomeric assembly of
solubilized pig gastric H/K-ATPase. J Biochem 138: 293301, 2005.
2. Abe K, Tani K, Fujiyoshi Y. Conformational rearrangement of gastric H,K-ATPase
induced by an acid suppressant. Nat Commun 2: 155, 2011.
3. Abe K, Tani K, Fujiyoshi Y. Structural and functional characterization of H,KATPase with bound fluorinated phosphate analogs. J Struct Biol 170: 60 68, 2010.
4. Abe K, Tani K, Nishizawa T, Fujiyoshi Y. Inter-subunit interaction of gastric H,KATPase prevents reverse reaction of the transport cycle. EMBO J 28: 16371643,
2009.
5. Abou-Samra AB, Juppner H, Force T, Freeman MW, Kong XF, Schipani E, Urena P,
Richards J, Bonventre JV, Potts JT Jr. Expression cloning of a common receptor for
parathyroid hormone and parathyroid hormone-related peptide from rat osteoblast-like cells: a single receptor stimulates intracellular accumulation of both cAMP
and inositol trisphosphates and increases intracellular free calcium. Proc Natl Acad Sci
USA 89: 27322736, 1992.
6. Abreo K, Adlakha A, Kilpatrick S, Flanagan R, Webb R, Shakamuri S. The milk-alkali
syndrome. A reversible form of acute renal failure. Arch Intern Med 153: 10051010,
1993.
7. Adams JS, Clemens TL, Parrish JA, Holick MF. Vitamin-D synthesis and metabolism
after ultraviolet irradiation of normal and vitamin-D-deficient subjects. N Engl J Med
306: 722725, 1982.
VI. CONCLUSIONS
8. Agnew JE, Holdsworth CD. The effect of fat on calcium absorption from a mixed
meal in normal subjects, patients with malabsorptive disease, and patients with a
partial gastrectomy. Gut 12: 973977, 1971.
238
DISCLOSURES
Pancreastatin exerts a variety of metabolic effects. Apart
from influencing energy metabolism, pancreasstatin was
shown to affect the secretion of PTH from the parathyroid
gland. In isolated bovine and porcine parathyroid cells,
pancreastatin has a clear inhibitory effect on PTH secretion
(282, 317, 911). The suppression of PTH functions on a
transcriptional level (1211). Reduced PTH secretion in turn
would have a potential impact on calcium and bone metabolism. Whether the same observations are valid for humans
is less clear, as pancreastatin failed to inhibit PTH secretion
from isolated human parathyroid cells (911). Regardless,
the volume of data on pancreastatin and its influence on the
parathyroid gland is very small, and further investigations
would be necessary to establish this intriguing link. Apart
from potential modulation of parathyroid secretion, pancreastatin has also been shown to have an inhibitory effect
on gastric acid secretion (655).
30. Anusaksathien O, Laplace C, Li X, Ren Y, Peng L, Goldring SR, Galson DL. Tissuespecific and ubiquitous promoters direct the expression of alternatively spliced transcripts from the calcitonin receptor gene. J Biol Chem 276: 2266322674, 2001.
31. Ardaillou R. Kidney and calcitonin. Nephron 15: 250 260, 1975.
12. Akey JM, Swanson WJ, Madeoy J, Eberle M, Shriver MD. TRPV6 exhibits unusual
patterns of polymorphism and divergence in worldwide populations. Hum Mol Genet
15: 2106 2113, 2006.
13. Akhter S, Kutuzova GD, Christakos S, DeLuca HF. Calbindin D9k is not required for
1,25-dihydroxyvitamin D3-mediated Ca2 absorption in small intestine. Arc Biochem
Biophys 460: 227232, 2007.
14. Akiyoshi-Shibata M, Sakaki T, Ohyama Y, Noshiro M, Okuda K, Yabusaki Y. Further
oxidation of hydroxycalcidiol by calcidiol 24-hydroxylase. A study with the mature
enzyme expressed in Escherichia coli. Eur J Biochem 224: 335343, 1994.
15. Al-Ansary D, Bogeski I, Disteldorf BMJ, Becherer U, Niemeyer BA. ATP modulates
Ca2 uptake by TRPV6 and is counteracted by isoform-specific phosphorylation.
FASEB J 24: 425 435, 2010.
16. Alam AS, Moonga BS, Bevis PJ, Huang CL, Zaidi M. Amylin inhibits bone resorption
by a direct effect on the motility of rat osteoclasts. Exp Physiol 78: 183196, 1993.
18. Allen LH. Calcium bioavailability and absorption: a review. Am J Clin Nutr 35: 783
808, 1982.
40. Arthur JM, Collinsworth GP, Gettys TW, Quarles LD, Raymond JR. Specific coupling
of a cation-sensing receptor to G protein -subunits in MDCK cells. Am J Physiol
Renal Physiol 273: F129 F135, 1997.
20. Aly A, Shulkes A, Baldwin GS. Short term infusion of glycine-extended gastrin(17)
stimulates both proliferation and formation of aberrant crypt foci in rat colonic
mucosa. Int J Cancer 94: 307313, 2001.
41. Asano S, Kawada K, Kimura T, Grishin AV, Caplan MJ, Takeguchi N. The roles of
carbohydrate chains of the beta-subunit on the functional expression of gastric
H,K-ATPase. J Biol Chem 275: 8324 8330, 2000.
21. Amling M, Priemel M, Holzmann T, Chapin K, Rueger JM, Baron R, Demay MB.
Rescue of the skeletal phenotype of vitamin D receptor-ablated mice in the setting of
normal mineral ion homeostasis: formal histomorphometric and biomechanical analyses. Endocrinology 140: 4982 4987, 1999.
22. Andersen BN. Species variation in the tyrosine sulfation of mammalian gastrins. Gen
Comp Endocrinol 58: 44 50, 1985.
23. Anderson NG, Hanson PJ. Involvement of calcium-sensitive phospholipid-dependent protein kinase in control of acid secretion by isolated rat parietal cells. Biochem
J 232: 609 611, 1985.
24. Andersson K, Cabero JL, Mattsson H, Hakanson R. Gastric acid secretion after
depletion of enterochromaffin-like cell histamine. A study with alpha-fluoromethylhistidine in rats. Scand J Gastroenterol 31: 24 30, 1996.
25. Andersson S, Chang D, Folkers K, Rosell S. Inhibition of gastric acid secretion in dogs
by neurotensin. Life Sci 19: 367370, 1976.
26. Andersson S, Davis DL, Dahlback H, Jornvall H, Russell DW. Cloning, structure, and
expression of the mitochondrial cytochrome P-450 sterol 26-hydroxylase, a bile acid
biosynthetic enzyme. J Biol Chem 264: 8222 8229, 1989.
27. Andreassen TT, Ejersted C, Oxlund H. Intermittent parathyroid hormone (134)
treatment increases callus formation and mechanical strength of healing rat fractures. J Bone Miner Res 14: 960 968, 1999.
28. Andreotti G, Mendez BL, Amodeo P, Morelli MA, Nakamuta H, Motta A. Structural
determinants of salmon calcitonin bioactivity: the role of the Leu-based amphipathic
alpha-helix. J Biol Chem 281: 2419324203, 2006.
29. Anisuzzaman AS, Morishima S, Suzuki F, Tanaka T, Muramatsu I. Identification of
M(1) muscarinic receptor subtype in rat stomach using a tissue segment binding
method, the effects of immobilization stress on the muscarinic receptors. Eur J
Pharmacol 599: 146 151, 2008.
43. Askew FA, Bruce HM, Callow RK, Philpot JS, Webster TA. Crystalline vitamin D.
Nature 128: 758, 1931.
44. Athmann C, Zeng N, Scott DR, Sachs G. Regulation of parietal cell calcium signaling
in gastric glands. Am J Physiol Gastrointest Liver Physiol 279: G1048 G1058, 2000.
45. Atkins GJ, Anderson PH, Findlay DM, Welldon KJ, Vincent C, Zannettino AC,
OLoughlin PD, Morris HA. Metabolism of vitamin D3 in human osteoblasts: evidence for autocrine and paracrine activities of 1 alpha,25-dihydroxyvitamin D3. Bone
40: 15171528, 2007.
46. Auchere D, Tardivel S, Gounelle JC, Drueke T, Lacour B. Role of transcellular
pathway in ileal Ca2 absorption: stimulation by low-Ca2 diet. Am J Physiol Gastrointest Liver Physiol 275: G951G956, 1998.
47. Auer J, Reeh PW, Fischer MJ. Acid-induced CGRP release from the stomach does not
depend on TRPV1 or ASIC3. Neurogastroenterol Motil 22: 680 687, 2010.
48. Awata H, Huang C, Handlogten ME, Miller RT. Interaction of the calcium-sensing
receptor and filamin, a potential scaffolding protein. J Biol Chem 276: 3487134879,
2001.
49. Axelson J, Persson P, Gagnemo-Persson R, Hakanson R. Importance of the stomach
in maintaining calcium homoeostasis in the rat. Gut 32: 1298 1302, 1991.
50. Axen E, Postlind H, Sjoberg H, Wikvall K. Liver mitochondrial cytochrome P450
CYP27 and recombinant-expressed human CYP27 catalyze 1-hydroxylation of
25-hydroxyvitamin D3. Proc Natl Acad Sci USA 91: 10014 10018, 1994.
51. Axen E, Postlind H, Wikvall K. Effects on CYP27 mRNA expression in rat kidney and
liver by 1,25-dihydroxyvitamin D3, a suppressor of renal 25-hydroxyvitamin D3
1-hydroxylase activity. Biochem Biophys Res Commun 215: 136 141, 1995.
239
17. Albrandt K, Brady EM, Moore CX, Mull E, Sierzega ME, Beaumont K. Molecular
cloning and functional expression of a third isoform of the human calcitonin receptor
and partial characterization of the calcitonin receptor gene. Endocrinology 136:
53775384, 1995.
74. Bell NJ, Burget D, Howden CW, Wilkinson J, Hunt RH. Appropriate acid suppression
for the management of gastro-oesophageal reflux disease. Digestion 51 Suppl 1:
59 67, 1992.
53. Bado A, Cloarec D, Moizo L, Laigneau JP, Bataille D, Lewin MJ. Neurotensin and
oxyntomodulin-(30 37) potentiate PYY regulation of gastric acid and somatostatin
secretions. Am J Physiol Gastrointest Liver Physiol 265: G113G117, 1993.
75. Bellido T, Ali AA, Plotkin LI, Fu Q, Gubrij I, Roberson PK, Weinstein RS, OBrien CA,
Manolagas SC, Jilka RL. Proteasomal degradation of Runx2 shortens parathyroid
hormone-induced anti-apoptotic signaling in osteoblasts. A putative explanation for
why intermittent administration is needed for bone anabolism. J Biol Chem 278:
50259 50272, 2003.
54. Bai M, Trivedi S, Brown EM. Dimerization of the extracellular calcium-sensing receptor (CaR) on the cell surface of CaR-transfected HEK293 cells. J Biol Chem 273:
2360523610, 1998.
55. Bai M, Trivedi S, Kifor O, Quinn SJ, Brown EM. Intermolecular interactions between
dimeric calcium-sensing receptor monomers are important for its normal function.
Proc Natl Acad Sci USA 96: 2834 2839, 1999.
56. Bai M, Trivedi S, Lane CR, Yang Y, Quinn SJ, Brown EM. Protein kinase C phosphorylation of threonine at position 888 in Ca2o-sensing receptor (CaR) inhibits coupling to Ca2 store release. J Biol Chem 273: 2126721275, 1998.
57. Bailey RL, Dodd KW, Goldman JA, Gahche JJ, Dwyer JT, Moshfegh AJ, Sempos CT,
Picciano MF. Estimation of total usual calcium and vitamin D intakes in the United
States. J Nutr 140: 817 822, 2010.
58. Baird IM, Oleesky S. Osteomalacia following gastric surgery. Gastroenterology 33:
284 292, 1957.
59. Baker AR, McDonnell DP, Hughes M, Crisp TM, Mangelsdorf DJ, Haussler MR, Pike
JW, Shine J, OMalley BW. Cloning and expression of full-length cDNA encoding
human vitamin D receptor. Proc Natl Acad Sci USA 85: 3294 3298, 1988.
61. Baldissera FG, Nielsen OV, Holst JJ. The intestinal mucosa preferentially releases
somatostatin-28 in pigs. Regul Pept 11: 251262, 1985.
62. Balesaria S, Sangha S, Walters JR. Human duodenum responses to vitamin D metabolites of TRPV6 and other genes involved in calcium absorption. Am J Physiol Gastrointest Liver Physiol 297: G1193G1197, 2009.
63. Barger G, Dale HH. The presence in ergot and physiological activity of beta-imidazolylethylamine. J Physiol 40: xxxviii-xl, 1910.
64. Barley NF, Howard A, OCallaghan D, Legon S, Walters JR. Epithelial calcium transporter expression in human duodenum. Am J Physiol Gastrointest Liver Physiol 280:
G285G290, 2001.
85. Bers DM, Ginsburg KS. Na:Ca stoichiometry and cytosolic Ca-dependent activation
of NCX in intact cardiomyocytes. Ann NY Acad Sci 1099: 326 338, 2007.
65. Basso D, Scrigner M, Toma A, Navaglia F, Di Mario F, Rugge M, Plebani M. Helicobacter pylori infection enhances mucosal interleukin-1 beta, interleukin-6, the soluble
receptor of interleukin-2. Int J Clin Lab Res 26: 207210, 1996.
86. Berthoud HR. Morphological analysis of vagal input to gastrin releasing peptide and
vasoactive intestinal peptide containing neurons in the rat glandular stomach. J Comp
Neurol 370: 6170, 1996.
67. Batzri S, Gardner JD. Cellular cyclic AMP in dispersed mucosal cells from guinea pig
stomach. Biochim Biophys Acta 541: 181189, 1978.
68. Bayliss WM, Starling EH. The mechanism of pancreatic secretion. J Physiol 28: 325
353, 1902.
69. Beales IL, Calam J. Inhibition of carbachol stimulated acid secretion by interleukin
1beta in rabbit parietal cells requires protein kinase C. Gut 48: 782789, 2001.
70. Beales IL, Calam J. Interleukin 1 beta and tumour necrosis factor alpha inhibit acid
secretion in cultured rabbit parietal cells by multiple pathways. Gut 42: 227234,
1998.
71. Beales IL, Ogunwobi OO. Glycine-extended gastrin inhibits apoptosis in Barretts
oesophageal and oesophageal adenocarcinoma cells through JAK2/STAT3 activation. J Mol Endocrinol 42: 305318, 2009.
88. Bertrand CA, Zhang R, Pilewski JM, Frizzell RA. SLC26A9 is a constitutively active,
CFTR-regulated anion conductance in human bronchial epithelia. J Gen Physiol 133:
421 438, 2009.
89. Besancon M, Shin JM, Mercier F, Munson K, Miller M, Hersey S, Sachs G. Membrane
topology and omeprazole labeling of the gastric H,K-adenosinetriphosphatase.
Biochemistry 32: 23452355, 1993.
90. Besancon M, Simon A, Sachs G, Shin JM. Sites of reaction of the gastric H-KATPase with extracytoplasmic thiol reagents. J Biol Chem 272: 22438 22446, 1997.
91. Bhattacharyya MH, DeLuca HF. The regulation of calciferol-25-hydroxylase in the
chick. Biochem Biophys Res Commun 59: 734 741, 1974.
92. Bhattacharyya MH, DeLuca HF. The regulation of rat liver calciferol-25-hydroxylase.
J Biol Chem 248: 2969 2973, 1973.
72. Beck L, Karaplis AC, Amizuka N, Hewson AS, Ozawa H, Tenenhouse HS. Targeted
inactivation of Npt2 in mice leads to severe renal phosphate wasting, hypercalciuria,
and skeletal abnormalities. Proc Natl Acad Sci USA 95: 53725377, 1998.
93. Bhattacharyya MH, DeLuca HF. Subcellular location of rat liver calciferol-25-hydroxylase. Arch Biochem Biophys 160: 58 62, 1974.
73. Beil W, Mannschedel W, Sewing KF. Protein kinase C and parietal cell function.
Biochem Biophys Res Commun 149: 720 728, 1987.
94. Bianco SD, Peng JB, Takanaga H, Suzuki Y, Crescenzi A, Kos CH, Zhuang L, Freeman
MR, Gouveia CH, Wu J, Luo H, Mauro T, Brown EM, Hediger MA. Marked distur-
240
60. Bakke I, Qvigstad G, Brenna E, Sandvik AK, Waldum HL. Gastrin has a specific
proliferative effect on the rat enterochromaffin-like cell, but not on the parietal cell:
a study by elutriation centrifugation. Acta Physiol Scand 169: 29 37, 2000.
76. Benn BS, Ajibade D, Porta A, Dhawan P, Hediger M, Peng JB, Jiang Y, Oh GT, Jeung
EB, Lieben L, Bouillon R, Carmeliet G, Christakos S. Active intestinal calcium transport in the absence of transient receptor potential vanilloid type 6 and calbindinD9k. Endocrinology 149: 3196 3205, 2008.
116. Booth BE, Tsai HC, Morris RC Jr. Vitamin D status regulates 25-hydroxyvitamin
D3-1 alpha-hydroxylase and its responsiveness to parathyroid hormone in the chick.
J Clin Invest 75: 155161, 1985.
117. Borthwick LA, Neal A, Hobson L, Gerke V, Robson L, Muimo R. The annexin
2S100A10 complex and its association with TRPV6 is regulated by cAMP/PKA/CnA
in airway and gut epithelia. Cell Calcium 44: 147157, 2008.
118. Bosl MR, Stein V, Hubner C, Zdebik AA, Jordt SE, Mukhopadhyay AK, Davidoff MS,
Holstein AF, Jentsch TJ. Male germ cells and photoreceptors, both dependent on
close cell-cell interactions, degenerate upon ClC-2 Cl channel disruption. EMBO J
20: 1289 1299, 2001.
119. Bouley R, Lu HA, Nunes P, Da Silva N, McLaughlin M, Chen Y, Brown D. Calcitonin
has a vasopressin-like effect on aquaporin-2 trafficking and urinary concentration. J
Am Soc Nephrol 22: 59 72, 2011.
120. Bourdeau A, Moutahir M, Souberbielle JC, Bonnet P, Herviaux P, Sachs C, Lieberherr M. Effects of lipoxygenase products of arachidonate metabolism on parathyroid
hormone secretion. Endocrinology 135: 1109 1112, 1994.
121. Bourdeau A, Souberbielle JC, Bonnet P, Herviaux P, Sachs C, Lieberherr M. Phospholipase-A2 action and arachidonic acid metabolism in calcium-mediated parathyroid hormone secretion. Endocrinology 130: 1339 1344, 1992.
122. Brandsborg M, Nielsen HE, Brandsborg O, Olsen KJ, Lovgreen NA. The role of
serum gastrin in the secretion of calcitonin: studies in patients with pernicious anaemia and in healthy subjects. Scand J Gastroenterol 15: 2328, 1980.
123. Brauer CA, Coca-Perraillon M, Cutler DM, Rosen AB. Incidence and mortality of hip
fractures in the United States. JAMA 302: 15731579, 2009.
124. Brazeau P, Vale W, Burgus R, Ling N, Butcher M, Rivier J, Guillemin R. Hypothalamic
polypeptide that inhibits the secretion of immunoreactive pituitary growth hormone. Science 179: 7779, 1973.
125. Brenza HL, DeLuca HF. Regulation of 25-hydroxyvitamin D3 1alpha-hydroxylase
gene expression by parathyroid hormone and 1,25-dihydroxyvitamin D3. Arch
Biochem Biophys 381: 143152, 2000.
126. Brewer HB Jr, Ronan R. Bovine parathyroid hormone: amino acid sequence. Proc
Natl Acad Sci USA 67: 18621869, 1970.
127. Bringhurst FR, Stern AM, Yotts M, Mizrahi N, Segre GV, Potts JT Jr. Peripheral
metabolism of PTH: fate of biologically active amino terminus in vivo. Am J Physiol
Endocrinol Metab 255: E886 E893, 1988.
128. Brommage R. Measurement of calcium and phosphorus fluxes during lactation in the
rat. J Nutr 119: 428 438, 1989.
129. Bronner F, Pansu D, Stein WD. An analysis of intestinal calcium transport across the
rat intestine. Am J Physiol Gastrointest Liver Physiol 250: G561G569, 1986.
130. Brossard JH, Cloutier M, Roy L, Lepage R, Gascon-Barre M, DAmour P. Accumulation of a non-(1 84) molecular form of parathyroid hormone (PTH) detected by
intact PTH assay in renal failure: importance in the interpretation of PTH values. J
Clin Endocrinol Metab 81: 39233929, 1996.
131. Brossard JH, Whittom S, Lepage R, DAmour P. Carboxyl-terminal fragments of
parathyroid hormone are not secreted preferentially in primary hyperparathyroidism as they are in other hypercalcemic conditions. J Clin Endocrinol Metab 77: 413
419, 1993.
112. Blunt JW, DeLuca HF, Schnoes HK. 25-Hydroxycholecalciferol. A biologically active
metabolite of vitamin D3. Biochemistry 7: 33173322, 1968.
132. Brown AJ, Krits I, Armbrecht HJ. Effect of age, vitamin D, and calcium on the
regulation of rat intestinal epithelial calcium channels. Arch Biochem Biophys 437:
5158, 2005.
113. Boel E, Vuust J, Norris F, Norris K, Wind A, Rehfeld JF, Marcker KA. Molecular
cloning of human gastrin cDNA: evidence for evolution of gastrin by gene duplication. Proc Natl Acad Sci USA 80: 2866 2869, 1983.
133. Brown E, Enyedi P, LeBoff M, Rotberg J, Preston J, Chen C. High extracellular Ca2
and Mg2 stimulate accumulation of inositol phosphates in bovine parathyroid cells.
FEBS Lett 218: 113118, 1987.
134. Brown EM, Gamba G, Riccardi D, Lombardi M, Butters R, Kifor O, Sun A, Hediger
MA, Lytton J, Hebert SC. Cloning and characterization of an extracellular Ca2sensing receptor from bovine parathyroid. Nature 366: 575580, 1993.
241
115. Boivin G, Mesguich P, Pike JW, Bouillon R, Meunier PJ, Haussler MR, Dubois PM,
Morel G. Ultrastructural immunocytochemical localization of endogenous 1,25-dihydroxyvitamin D3 and its receptors in osteoblasts and osteocytes from neonatal
mouse and rat calvaria. Bone Miner 3: 125136, 1987.
156. Care AD, Bruce JB, Boelkins J, Kenny AD, Conaway H, Anast CS. Role of pancreozymin-cholecystokinin and structurally related compounds as calcitonin secretogogues. Endocrinology 89: 262271, 1971.
157. Carles-Bonnet C, Jarrousse C, Niel H, Martinez J, Bataille D. Oxyntomodulin and its
(19 37) and (30 37) fragments inhibit histamine-stimulated gastric acid secretion in
the conscious rat. Eur J Pharmacol 203: 245252, 1991.
158. Carney S, Thompson L. Acute effect of calcitonin on rat renal electrolyte transport.
Am J Physiol Renal Fluid Electrolyte Physiol 240: F12F16, 1981.
159. Carney SL. Acute effect of endogenous calcitonin on rat renal function. Miner Electrolyte Metab 21: 411 416, 1995.
160. Carney SL. Calcitonin and human renal calcium and electrolyte transport. Miner
Electrolyte Metab 23: 43 47, 1997.
161. Carraway R, Leeman SE. The isolation of a new hypotensive peptide, neurotensin,
from bovine hypothalami. J Biol Chem 248: 6854 6861, 1973.
140. Buchan AM, MacLeod MD, Meloche RM, Kwok YN. Muscarinic regulation of somatostatin release from primary cultures of human antral epithelial cells. Pharmacology
44: 33 40, 1992.
162. Carrillo-Lopez N, Alvarez-Hernandez D, Gonzalez-Suarez I, Roman-Garcia P, Valdivielso JM, Fernandez-Martin JL, Cannata-Andia JB. Simultaneous changes in the
calcium-sensing receptor and the vitamin D receptor under the influence of calcium
and calcitriol. Nephrol Dial Transplant 23: 3479 3484, 2008.
141. Buchan AM, Meloche RM, Kwok YN, Kofod H. Effect of cholecystokinin and secretin
on somatostatin release from cultured antral cells. Gastroenterology 104: 1414
1419, 1993.
163. Caterina MJ, Rosen TA, Tominaga M, Brake AJ, Julius D. A capsaicin-receptor homologue with a high threshold for noxious heat. Nature 398: 436 441, 1999.
142. Buchan AM, Squires PE, Ring M, Meloche RM. Mechanism of action of the calciumsensing receptor in human antral gastrin cells. Gastroenterology 120: 1128 1139,
2001.
165. Ceglia L, Harris SS, Rasmussen HM, Dawson-Hughes B. Activation of the calcium
sensing receptor stimulates gastrin and gastric acid secretion in healthy participants.
Osteoporos Int 20: 7178, 2009.
166. Chabardes D, Gagnan-Brunette M, Imbert-Teboul M, Gontcharevskaia O, Montegut M, Clique A, Morel F. Adenylate cyclase responsiveness to hormones in various portions of the human nephron. J Clin Invest 65: 439 448, 1980.
167. Chabre O, Conklin BR, Lin HY, Lodish HF, Wilson E, Ives HE, Catanzariti L, Hemmings BA, Bourne HR. A recombinant calcitonin receptor independently stimulates
3=,5=-cyclic adenosine monophosphate and Ca2/inositol phosphate signaling pathways. Mol Endocrinol 6: 551556, 1992.
168. Chai SY, Christopoulos G, Cooper ME, Sexton PM. Characterization of binding sites
for amylin, calcitonin, and CGRP in primate kidney. Am J Physiol Renal Physiol 274:
F51F62, 1998.
169. Chambers TJ, Magnus CJ. Calcitonin alters behaviour of isolated osteoclasts. J Pathol
136: 2739, 1982.
170. Chang Q, Hoefs S, van der Kemp AW, Topala CN, Bindels RJ, Hoenderop JG. The
beta-glucuronidase klotho hydrolyzes and activates the TRPV5 channel. Science 310:
490 493, 2005.
171. Chang W, Tu C, Chen TH, Bikle D, Shoback D. The extracellular calcium-sensing
receptor (CaSR) is a critical modulator of skeletal development. Sci Signal 1: ra1,
2008.
172. Chang W, Tu C, Chen TH, Komuves L, Oda Y, Pratt SA, Miller S, Shoback D.
Expression and signal transduction of calcium-sensing receptors in cartilage and
bone. Endocrinology 140: 58835893, 1999.
173. Chattopadhyay N, Cheng I, Rogers K, Riccardi D, Hall A, Diaz R, Hebert SC, Soybel
DI, Brown EM. Identification and localization of extracellular Ca2-sensing receptor
in rat intestine. Am J Physiol Gastrointest Liver Physiol 274: G122G130, 1998.
174. Chattopadhyay N, Yano S, Tfelt-Hansen J, Rooney P, Kanuparthi D, Bandyopadhyay
S, Ren X, Terwilliger E, Brown EM. Mitogenic action of calcium-sensing receptor on
rat calvarial osteoblasts. Endocrinology 145: 34513462, 2004.
154. Cantley LK, Russell J, Lettieri D, Sherwood LM. 1,25-Dihydroxyvitamin D3 suppresses parathyroid hormone secretion from bovine parathyroid cells in tissue culture. Endocrinology 117: 2114 2119, 1985.
175. Chen CJ, Barnett JV, Congo DA, Brown EM. Divalent cations suppress 3=,5=-adenosine monophosphate accumulation by stimulating a pertussis toxin-sensitive guanine nucleotide-binding protein in cultured bovine parathyroid cells. Endocrinology
124: 233239, 1989.
155. Care AD, Bates RF, Swaminathan R, Ganguli PC. The role of gastrin as a calcitonin
secretagogue. J Endocrinol 51: 735744, 1971.
176. Chen D, Marvik R, Ronning K, Andersson K, Waldum HL, Hakanson R. Gastrinevoked secretion of pancreastatin and histamine from ECL cells and of acid from
242
139. Bu FX, Armas L, Lappe J, Zhou Y, Gao G, Wang HW, Recker R, Zhao LJ. Comprehensive association analysis of nine candidate genes with serum 25-hydroxy vitamin
D levels among healthy Caucasian subjects. Hum Genet 128: 549 556, 2010.
180. Chen KS, DeLuca HF. Cloning of the human 1 alpha,25-dihydroxyvitamin D-3 24hydroxylase gene promoter and identification of two vitamin D-responsive elements. Biochim Biophys Acta 1263: 19, 1995.
201. Chirayath MV, Gajdzik L, Hulla W, Graf J, Cross HS, Peterlik M. Vitamin D increases
tight-junction conductance and paracellular Ca2 transport in Caco-2 cell cultures.
Am J Physiol Gastrointest Liver Physiol 274: G389 G396, 1998.
181. Chen S, Glenn DJ, Ni W, Grigsby CL, Olsen K, Nishimoto M, Law CS, Gardner DG.
Expression of the vitamin d receptor is increased in the hypertrophic heart. Hypertension 52: 1106 1112, 2008.
202. Chiu HF, Huang YW, Chang CC, Yang CY. Use of proton pump inhibitors increased
the risk of hip fracture: a population-based case-control study. Pharmacoepidemiol
Drug Safety 19: 11311136, 2010.
182. Cheng I, Qureshi I, Chattopadhyay N, Qureshi A, Butters RR, Hall AE, Cima RR,
Rogers KV, Hebert SC, Geibel JP, Brown EM, Soybel DI. Expression of an extracellular calcium-sensing receptor in rat stomach. Gastroenterology 116: 118 126, 1999.
183. Cheng JB, Levine MA, Bell NH, Mangelsdorf DJ, Russell DW. Genetic evidence that
the human CYP2R1 enzyme is a key vitamin D 25-hydroxylase. Proc Natl Acad Sci
USA 101: 77117715, 2004.
204. Chuang CN, Tanner M, Lloyd KC, Wong H, Soll AH. Endogenous somatostatin
inhibits histamine release from canine gastric mucosal cells in primary culture. Am J
Physiol Gastrointest Liver Physiol 265: G521G525, 1993.
184. Cheng JB, Motola DL, Mangelsdorf DJ, Russell DW. De-orphanization of cytochrome P450 2R1: a microsomal vitamin D 25-hydroxilase. J Biol Chem 278: 38084
38093, 2003.
205. Chung I, Li P, Lee K, Chang T, Chey WY. Dual inhibitory mechanism of secretin
action on acid secretion in totally isolated, vascularly perfused rat stomach. Gastroenterology 107: 17511758, 1994.
185. Cheng SX, Geibel JP, Hebert SC. Extracellular polyamines regulate fluid secretion in
rat colonic crypts via the extracellular calcium-sensing receptor. Gastroenterology
126: 148 158, 2004.
206. Chung MK, Guler AD, Caterina MJ. TRPV1 shows dynamic ionic selectivity during
agonist stimulation. Nat Neurosci 11: 555564, 2008.
186. Cheng SX, Okuda M, Hall AE, Geibel JP, Hebert SC. Expression of calcium-sensing
receptor in rat colonic epithelium: evidence for modulation of fluid secretion. Am J
Physiol Gastrointest Liver Physiol 283: G240 G250, 2002.
187. Chesney RW, Rosen JF, Hamstra AJ, Smith C, Mahaffey K, DeLuca HF. Absence of
seasonal variation in serum concentrations of 1,25-dihydroxyvitamin D despite a rise
in 25-hydroxyvitamin D in summer. J Clin Endocrinol Metab 53: 139 142, 1981.
188. Cheung R, Erclik MS, Mitchell J. Increased expression of G11alpha in osteoblastic
cells enhances parathyroid hormone activation of phospholipase C and AP-1 regulation of matrix metalloproteinase-13 mRNA. J Cell Physiol 204: 336 343, 2005.
189. Chew CS. Cholecystokinin, carbachol, gastrin, histamine, and forskolin increase
[Ca2]i in gastric glands. Am J Physiol Gastrointest Liver Physiol 250: G814 G823,
1986.
190. Chew CS, Brown MR. Release of intracellular Ca2 and elevation of inositol trisphosphate by secretagogues in parietal and chief cells isolated from rabbit gastric mucosa. Biochim Biophys Acta 888: 116 125, 1986.
191. Chey WY, Chang CH, Pan HJ, Chang C, Kim BM, Park IS, Chang TM. Evidence on
the presence of secretin cells in the gastric antral and oxyntic mucosa. Regul Pept 111:
183190, 2003.
192. Chey WY, Chang TM, Park HJ, Lee KY, Escoffery R. Secretin-like immunoreactivity
and biological activity in the antral mucosa. Endocrinology 113: 651 656, 1983.
193. Chey WY, Escoffery R. Secretion cells in the gastrointestinal tract. Endocrinology 98:
1390 1395, 1976.
194. Chey WY, Hitanant S, Hendricks J, Lorber SH. Effect of secretin and cholecystokinin
on gastric emptying and gastric secretion in man. Gastroenterology 58: 820 827,
1970.
207. Cid LP, Montrose-Rafizadeh C, Smith DI, Guggino WB, Cutting GR. Cloning of a
putative human voltage-gated chloride channel (CIC-2) cDNA widely expressed in
human tissues. Hum Mol Genet 4: 407 413, 1995.
208. Clark CG, Crooks J, Dawson AA, Mitchell PE. Disordered calcium metabolism after
polya partial gastrectomy. Lancet 1: 734 738, 1964.
209. Clemens TL, Adams JS, Henderson SL, Holick MF. Increased skin pigment reduces
the capacity of skin to synthesise vitamin D3. Lancet 1: 74 76, 1982.
210. Clements MR, Davies M, Fraser DR, Lumb GA, Mawer EB, Adams PH. Metabolic
inactivation of vitamin D is enhanced in primary hyperparathyroidism. Clin Sci 73:
659 664, 1987.
211. Clements MR, Davies M, Hayes ME, Hickey CD, Lumb GA, Mawer EB, Adams PH.
The role of 1,25-dihydroxyvitamin D in the mechanism of acquired vitamin D deficiency. Clin Endocrinol 37: 1727, 1992.
212. Clements MR, Johnson L, Fraser DR. A new mechanism for induced vitamin D
deficiency in calcium deprivation. Nature 325: 62 65, 1987.
213. Cleve H. The variants of the group-specific component. A review of their distribution in human populations. Isr J Med Sci 9: 11331146, 1973.
214. Cocchi D, Maccarinelli G, Sibilia V, Tulipano G, Torsello A, Pazzaglia UE, Giustina A,
Netti C. GH-releasing peptides and bone. J Endocrinol Invest 28: 1114, 2005.
215. Cochran M, Peacock M, Sachs G, Nordin BE. Renal effects of calcitonin. Br Med J 1:
135137, 1970.
216. Collip JB. The extraction of a parathyroid hormone which will prevent or control
parathyroid tetany and which regulates the level of blood calcium. J Biol Chem 63:
395 438, 1925.
195. Chey WY, Lee YH, Hendricks JG, Rhodes RA, Tai HH. Plasma secretin concentrations in fasting and postprandial state in man. Am J Dig Dis 23: 981988, 1978.
196. Chiba T, Fisher SK, Agranoff BW, Yamada T. Autoregulation of muscarinic and
gastrin receptors on gastric parietal cells. Am J Physiol Gastrointest Liver Physiol 256:
G356 G363, 1989.
218. Committee to Review Dietary Reference Intakes for Vitamin D and Calcium. Dietary
Reference Intakes for Calcium and Vitamin D. Washington, DC: National Academy
Press, 2010.
243
179. Chen D, Zhao CM, Hakanson R, Samuelson LC, Rehfeld JF, Friis-Hansen L. Altered
control of gastric acid secretion in gastrin-cholecystokinin double mutant mice. Gastroenterology 126: 476 487, 2004.
224. Cooper CW, McGuigan JE, Schwesinger WH, Brubaker RL, Munson PL. Correlation
between levels of gastrin and thyrocalcitonin in pig thyroid venous blood. Endocrinology 95: 302307, 1974.
244. Davies M, Heys SE, Selby PL, Berry JL, Mawer EB. Increased catabolism of 25hydroxyvitamin D in patients with partial gastrectomy and elevated 1,25-dihydroxyvitamin D levels. Implications for metabolic bone disease. J Clin Endocrinol
Metab 82: 209 212, 1997.
225. Cooper CW, Ramp WK, Becker DI, Ontjes DA. In vitro secretion of immunoreactive
rat thyrocalcitonin. Endocrinology 101: 304 311, 1977.
245. Davies M, Mawer EB, Krawitt EL. Comparative absorption of vitamin D3 and 25hydroxyvitamin D3 in intestinal disease. Gut 21: 287292, 1980.
226. Cooper CW, Schwesinger WH, Mahgoub AM, Ontjes DA. Thyrocalcitonin: stimulation of secretion by pentagastrin. Science 172: 1238 1240, 1971.
227. Copp DH, Cameron EC, Cheney BA, Davidson AG, Henze KG. Evidence for calcitonin: a new hormone from the parathyroid that lowers blood calcium. Endocrinology
70: 638 649, 1962.
229. Cornish J, Callon KE, Bava U, Kamona SA, Cooper GJ, Reid IR. Effects of calcitonin,
amylin, calcitonin gene-related peptide on osteoclast development. Bone 29: 162
168, 2001.
230. Couper RT, Corey M, Moore DJ, Fisher LJ, Forstner GG, Durie PR. Decline of
exocrine pancreatic function in cystic fibrosis patients with pancreatic sufficiency.
Pediatr Res 32: 179 182, 1992.
231. Cramer T, Juttner S, Plath T, Mergler S, Seufferlein T, Wang TC, Merchant J, Hocker
M. Gastrin transactivates the chromogranin A gene through MEK-1/ERK- and PKCdependent phosphorylation of Sp1 and CREB. Cell Signal 20: 60 72, 2008.
232. Cuppoletti J, Sachs G. Regulation of gastric acid secretion via modulation of a chloride conductance. J Biol Chem 259: 1495214959, 1984.
233. DAmour P, Brossard JH, Rousseau L, Nguyen-Yamamoto L, Nassif E, Lazure C,
Gauthier D, Lavigne JR, Zahradnik RJ. Structure of non-(1 84) PTH fragments secreted by parathyroid glands in primary and secondary hyperparathyroidism. Kidney
Int 68: 998 1007, 2005.
234. DAmour P, Segre GV, Roth SI, Potts JT Jr. Analysis of parathyroid hormone and its
fragments in rat tissues: chemical identification and microscopical localization. J Clin
Invest 63: 89 98, 1979.
235. Dahlback H, Wikvall K. 25-Hydroxylation of vitamin D3 by a cytochrome P-450 from
rabbit liver mitochondria. Biochem J 252: 207213, 1988.
236. Daiger SP, Schanfield MS, Cavalli-Sforza LL. Group-specific component (Gc) proteins bind vitamin D and 25-hydroxyvitamin D. Proc Natl Acad Sci USA 72: 2076
2080, 1975.
237. Dale HH, Laidlow PP. The physiological action of beta-iminazolylethylamine. J Physiol
41: 318 344, 1910.
238. Dardenne O, Prudhomme J, Arabian A, Glorieux FH, St-Arnaud R. Targeted inactivation of the 25-hydroxyvitamin D(3)-1(alpha)-hydroxylase gene (CYP27B1) creates an animal model of pseudovitamin D-deficiency rickets. Endocrinology 142:
31353141, 2001.
239. Dardenne O, Prudhomme J, Hacking SA, Glorieux FH, St-Arnaud R. Correction of
the abnormal mineral ion homeostasis with a high-calcium, high-phosphorus, highlactose diet rescues the PDDR phenotype of mice deficient for the 25-hydroxyvitamin D-1alpha-hydroxylase (CYP27B1). Bone 32: 332340, 2003.
244
247. Davis WL, Jones RG. Lysosomal proliferation in rachitic avian intestinal absorptive
cells following 1,25-dihydroxycholecalciferol. Tissue Cell 14: 585595, 1982.
248. De Groot T, Kovalevskaya NV, Verkaart S, Schilderink N, Felici M, van der Hagen
EA, Bindels RJ, Vuister GW, Hoenderop JG. Molecular mechanisms of calmodulin
action on TRPV5 and modulation by parathyroid hormone. Mol Cell Biol 31: 2845
2853, 2011.
249. De Groot T, Lee K, Langeslag M, Xi Q, Jalink K, Bindels RJ, Hoenderop JG. Parathyroid hormone activates TRPV5 via PKA-dependent phosphorylation. J Am Soc Nephrol 20: 16931704, 2009.
250. De Jesus Ferreira MC, Helies-Toussaint C, Imbert-Teboul M, Bailly C, Verbavatz JM,
Bellanger AC, Chabardes D. Co-expression of a Ca2-inhibitable adenylyl cyclase
and of a Ca2-sensing receptor in the cortical thick ascending limb cell of the rat
kidney. Inhibition of hormone-dependent cAMP accumulation by extracellular
Ca2. J Biol Chem 273: 1519215202, 1998.
251. De Rouffignac C, Elalouf JM. Effects of calcitonin on the renal concentrating mechanism. Am J Physiol Renal Fluid Electrolyte Physiol 245: F506 F511, 1983.
252. De Vries F, Cooper AL, Cockle SM, Van Staa TP, Cooper C. Fracture risk in patients
receiving acid-suppressant medication alone and in combination with bisphosphonates. Osteoporosis Int 20: 1989 1998, 2009.
253. Dedek K, Waldegger S. Colocalization of KCNQ1/KCNE channel subunits in the
mouse gastrointestinal tract. Pflgers Arch 442: 896 902, 2001.
254. Delhanty PJ, van der Eerden BC, van der Velde M, Gauna C, Pols HA, Jahr H, Chiba
H, van der Lely AJ, van Leeuwen JP. Ghrelin and unacylated ghrelin stimulate human
osteoblast growth via mitogen-activated protein kinase (MAPK)/phosphoinositide
3-kinase (PI3K) pathways in the absence of GHS-R1a. J Endocrinol 188: 37 47, 2006.
255. Deller DJ. Radiocalcium absorption after partial gastrectomy. Am J Dig Dis 11: 10 19,
1966.
256. DeLuca HF, Lund J, Rosenbloom A, Lobeck CC. Metabolism of tritiated vitamin D3
in familial vitamin D-resistant rickets with hypophosphatemia. J Pediatr 70: 828 832,
1967.
257. DelValle J, Yamada T. Amino acids and amines stimulate gastrin release from canine
antral G-cells via different pathways. J Clin Invest 85: 139 143, 1990.
258. Delvin EE, Arabian A, Glorieux FH. Kinetics of liver microsomal cholecalciferol
25-hydroxylase in vitamin D-depleted and -repleated rats. Biochem J 172: 417 422,
1978.
259. Demarest JR, Loo DD, Sachs G. Activation of apical chloride channels in the gastric
oxyntic cell. Science 245: 402 404, 1989.
260. Dempster DW, Hughes-Begos CE, Plavetic-Chee K, Brandao-Burch A, Cosman F,
Nieves J, Neubort S, Lu SS, Iida-Klein A, Arnett T, Lindsay R. Normal human oste-
228. Corley DA, Kubo A, Zhao W, Quesenberry C. Proton pump inhibitors and histamine-2 receptor antagonists are associated with hip fractures among at-risk patients.
Gastroenterology 139: 93101, 2010.
246. Davies SL, Ozawa A, McCormick WD, Dvorak MM, Ward DT. Protein kinase
C-mediated phosphorylation of the calcium-sensing receptor is stimulated by receptor activation and attenuated by calyculin-sensitive phosphatase activity. J Biol Chem
282: 15048 15056, 2007.
280. Dorrington KJ, Hui A, Hofmann T, Hitchman AJ, Harrison JE. Porcine intestinal
calcium-binding protein. Molecular properties and the effect of binding calcium ions.
J Biol Chem 249: 199 204, 1974.
282. Drees BM, Hamilton JW. Pancreastatin and bovine parathyroid cell secretion. Bone
Miner 17: 335346, 1992.
263. Derler I, Hofbauer M, Kahr H, Fritsch R, Muik M, Kepplinger K, Hack ME, Moritz S,
Schindl R, Groschner K, Romanin C. Dynamic but not constitutive association of
calmodulin with rat TRPV6 channels enables fine tuning of Ca2-dependent inactivation. J Physiol 577: 31 44, 2006.
264. Desfleurs E, Wittner M, Simeone S, Pajaud S, Moine G, Rajerison R, Di Stefano A.
Calcium-sensing receptor: regulation of electrolyte transport in the thick ascending
limb of Henles loop. Kidney Blood Press Res 21: 401 412, 1998.
283. Drescher D, DeLuca HF. Vitamin D stimulated calcium binding protein from rat
intestinal mucosa. Purification and some properties. Biochemistry 10: 23022307,
1971.
284. Dressman JB, Berardi RR, Dermentzoglou LC, Russell TL, Schmaltz SP, Barnett JL,
Jarvenpaa KM. Upper gastrointestinal (GI) pH in young, healthy men and women.
Pharm Res 7: 756 761, 1990.
285. Dubrasquet M, Bataille D, Gespach C. Oxyntomodulin (glucagon-37 or bioactive
enteroglucagon): a potent inhibitor of pentagastrin-stimulated acid secretion in rats.
Biosci Rep 2: 391395, 1982.
286. Dueland S, Helgerud P, Pedersen JI, Berg T, Drevon CA. Plasma clearance, transfer,
and distribution of vitamin D3 from intestinal lymph. Am J Physiol Endocrinol Metab
245: E326 E331, 1983.
266. Diamond JM, Bossert WH. Standing-gradient osmotic flow. A mechanism for coupling of water and solute transport in epithelia. J Gen Physiol 50: 20612083, 1967.
287. Dueland S, Pedersen JI, Helgerud P, Drevon CA. Absorption, distribution, transport
of vitamin D3 and 25-hydroxyvitamin D3 in the rat. Am J Physiol Endocrinol Metab 245:
E463E467, 1983.
268. Dimaline R, Sandvik AK. Histidine decarboxylase gene expression in rat fundus is
regulated by gastrin. FEBS Lett 281: 20 22, 1991.
269. Dinoso V, Chey WY, Hendricks J, Lorber SH. Intestinal mucosal hormones and
motor function of the stomach in man. J Appl Physiol 26: 326 329, 1969.
270. Divieti P, Geller AI, Suliman G, Juppner H, Bringhurst FR. Receptors specific for the
carboxyl-terminal region of parathyroid hormone on bone-derived cells: determinants of ligand binding and bioactivity. Endocrinology 146: 18631870, 2005.
271. Divieti P, Inomata N, Chapin K, Singh R, Juppner H, Bringhurst FR. Receptors for the
carboxyl-terminal region of pth(1 84) are highly expressed in osteocytic cells. Endocrinology 142: 916 925, 2001.
272. Divieti P, John MR, Juppner H, Bringhurst FR. Human PTH-(7 84) inhibits bone
resorption in vitro via actions independent of the type 1 PTH/PTHrP receptor.
Endocrinology 143: 171176, 2002.
273. Dixon KM, Deo SS, Norman AW, Bishop JE, Halliday GM, Reeve VE, Mason RS. In
vivo relevance for photoprotection by the vitamin D rapid response pathway. J
Steroid Biochem Mol Biol 103: 451 456, 2007.
274. Dobnig H, Turner RT. The effects of programmed administration of human parathyroid hormone fragment (134) on bone histomorphometry and serum chemistry
in rats. Endocrinology 138: 4607 4612, 1997.
275. Dong H, Sellers ZM, Smith A, Chow JY, Barrett KE. Na/Ca2 exchange regulates
Ca2-dependent duodenal mucosal ion transport and HCO3 secretion in mice. Am
J Physiol Gastrointest Liver Physiol 288: G457G465, 2005.
276. Dornonville de la Cour C, Bjorkqvist M, Sandvik AK, Bakke I, Zhao CM, Chen D,
Hakanson R. A-like cells in the rat stomach contain ghrelin and do not operate under
gastrin control. Regul Pept 99: 141150, 2001.
277. Dornonville de la Cour C, Lindqvist A, Egecioglu E, Tung YC, Surve V, Ohlsson C,
Jansson JO, Erlanson-Albertsson C, Dickson SL, Hakanson R. Ghrelin treatment
reverses the reduction in weight gain and body fat in gastrectomised mice. Gut 54:
907913, 2005.
288. Dueland S, Pedersen JI, Helgerud P, Drevon CA. Transport of vitamin D3 from rat
intestine. Evidence for transfer of vitamin D3 from chylomicrons to alpha-globulins.
J Biol Chem 257: 146 150, 1982.
289. Duflos C, Bellaton C, Baghdassarian N, Gadoux M, Pansu D, Bronner F. 1,25Dihydroxycholecalciferol regulates rat intestinal calbindin D9k posttranscriptionally.
J Nutr 126: 834 841, 1996.
290. Duflos C, Bellaton C, Pansu D, Bronner F. Calcium solubility, intestinal sojourn time
and paracellular permeability codetermine passive calcium absorption in rats. J Nutr
125: 2348 2355, 1995.
291. Dufner MM, Kirchhoff P, Remy C, Hafner P, Muller MK, Cheng SX, Tang LQ, Hebert
SC, Geibel JP, Wagner CA. The calcium-sensing receptor acts as a modulator of
gastric acid secretion in freshly isolated human gastric glands. Am J Physiol Gastrointest Liver Physiol 289: G1084 G1090, 2005.
292. Duman JG, Pathak NJ, Ladinsky MS, McDonald KL, Forte JG. Three-dimensional
reconstruction of cytoplasmic membrane networks in parietal cells. J Cell Sci 115:
12511258, 2002.
293. Duman JG, Tyagarajan K, Kolsi MS, Moore HP, Forte JG. Expression of rab11a N124I
in gastric parietal cells inhibits stimulatory recruitment of the H-K-ATPase. Am J
Physiol Cell Physiol 277: C361C372, 1999.
294. Durr KL, Abe K, Tavraz NN, Friedrich T. E2P state stabilization by the N-terminal
tail of the H-K-ATPase beta-subunit is critical for efficient proton pumping under
in vivo conditions. J Biol Chem 284: 2014720154, 2009.
295. DuVal JW, Saffouri B, Weir GC, Walsh JH, Arimura A, Makhlouf GM. Stimulation of
gastrin and somatostatin secretion from the isolated rat stomach by bombesin. Am J
Physiol Gastrointest Liver Physiol 241: G242G247, 1981.
296. Dvorak MM, Chen TH, Orwoll B, Garvey C, Chang W, Bikle DD, Shoback DM.
Constitutive activity of the osteoblast Ca2-sensing receptor promotes loss of cancellous bone. Endocrinology 148: 3156 3163, 2007.
297. Dvorak MM, Siddiqua A, Ward DT, Carter DH, Dallas SL, Nemeth EF, Riccardi D.
Physiological changes in extracellular calcium concentration directly control osteoblast function in the absence of calciotropic hormones. Proc Natl Acad Sci USA 101:
5140 5145, 2004.
298. Edkins JS. The chemical mechanism of gastric secretion. J Physiol 34: 133144, 1906.
299. Edwards BR, Baer PG, Sutton RA, Dirks JH. Micropuncture study of diuretic effects
on sodium and calcium reabsorption in the dog nephron. J Clin Invest 52: 2418 2427,
1973.
300. Edwards BR, Sutton RA, Dirks JH. Effect of calcium infusion on renal tubular reabsorption in the dog. Am J Physiol 227: 1318, 1974.
245
267. Dicker F, Quitterer U, Winstel R, Honold K, Lohse MJ. Phosphorylation-independent inhibition of parathyroid hormone receptor signaling by G protein-coupled
receptor kinases. Proc Natl Acad Sci USA 96: 5476 5481, 1999.
310. Ericsson P, Hakanson R, Rehfeld JF, Norlen P. Gastrin release: antrum microdialysis
reveals a complex neural control. Regul Pept 161: 2232, 2010.
311. Erler I, Hirnet D, Wissenbach U, Flockerzi V, Niemeyer BA. Ca2-selective transient receptor potential V channel architecture and function require a specific
ankyrin repeat. J Biol Chem 279: 34456 34463, 2004.
312. Esplugues JV, Barrachina MD, Calatayud S, Pique JM, Whittle BJ. Nitric oxide mediates the inhibition by interleukin-1 beta of pentagastrin-stimulated rat gastric acid
secretion. Br J Pharmacol 108: 9 10, 1993.
332. Force T, Bonventre JV, Flannery MR, Gorn AH, Yamin M, Goldring SR. A cloned
porcine renal calcitonin receptor couples to adenylyl cyclase and phospholipase C.
Am J Physiol Renal Fluid Electrolyte Physiol 262: F1110 F1115, 1992.
313. Fahrmann M, Kaufhold M, Pfeiffer AF, Seidler U. Protein kinase C-alpha attenuates
cholinergically stimulated gastric acid secretion of rabbit parietal cells. Br J Pharmacol
139: 545554, 2003.
334. Forster IC, Hernando N, Biber J, Murer H. Proximal tubular handling of phosphate:
a molecular perspective. Kidney Int 70: 1548 1559, 2006.
335. Forte JG, Forte GM, Saltman P. K-stimulated phosphatase of microsomes from
gastric mucosa. J Cell Physiol 69: 293304, 1967.
336. Forte JG, Zhu L. Apical recycling of the gastric parietal cell H-K-ATPase. Annu Rev
Physiol 72: 273296, 2010.
337. Fox J, Green DT. Direct effects of calcium channel blockers on duodenal calcium
transport in vivo. Eur J Pharmacol 129: 159 164, 1986.
338. Fraser DR, Kodicek E. Regulation of 25-hydroxycholecalciferol-1-hydroxylase activity in kidney by parathyroid hormone. Nat New Biol 241: 163166, 1973.
339. Fraser DR, Kodicek E. Unique biosynthesis by kidney of a biological active vitamin D
metabolite. Nature 228: 764 766, 1970.
340. Freeman MW, Wiren KM, Rapoport A, Lazar M, Potts JT Jr, Kronenberg HM.
Consequences of amino-terminal deletions of preproparathyroid hormone signal
sequence. Mol Endocrinol 1: 628 638, 1987.
319. FDA. FDA Drug Safety Communication: possible increased risk of fractures of the
hip, wrist, and spine with the use of proton pump inhibitors Food and Drug Administration. http://www.fda.gov/drugs/drugsafety/postmarketdrugsafetyinformation
forpatientsandproviders/ucm213206.htm [retrieved July 2011].
341. Freeman TC, Howard A, Bentsen BS, Legon S, Walters JR. Cellular and regional
expression of transcripts of the plasma membrane calcium pump PMCA1 in rabbit
intestine. Am J Physiol Gastrointest Liver Physiol 269: G126 G131, 1995.
320. Federico A, Dotti MT, Lore F, Nuti R. Cerebrotendinous xanthomatosis: pathophysiological study on bone metabolism. J Neurol Sci 115: 6770, 1993.
342. Friedman J, Au WY, Raisz LG. Responses of fetal rat bone to thyrocalcitonin in tissue
culture. Endocrinology 82: 149 156, 1968.
343. Friedman J, Raisz LG. Thyrocalcitonin: inhibitor of bone resorption in tissue culture.
Science 150: 14651467, 1965.
246
309. Engqvist-Goldstein AE, Warren RA, Kessels MM, Keen JH, Heuser J, Drubin DG.
The actin-binding protein Hip1R associates with clathrin during early stages of
endocytosis and promotes clathrin assembly in vitro. J Cell Biol 154: 1209 1223,
2001.
322. Feher JJ, Fullmer CS, Wasserman RH. Role of facilitated diffusion of calcium by
calbindin in intestinal calcium absorption. Am J Physiol Cell Physiol 262: C517C526,
1992.
364. Garland FC, Garland CF, Gorham ED, Young JF. Geographic variation in breast
cancer mortality in the United States: a hypothesis involving exposure to solar radiation. Prev Med 19: 614 622, 1990.
365. Garner SC, Pi M, Tu Q, Quarles LD. Rickets in cation-sensing receptor-deficient
mice: an unexpected skeletal phenotype. Endocrinology 142: 3996 4005, 2001.
366. Garrett JE, Capuano IV, Hammerland LG, Hung BC, Brown EM, Hebert SC, Nemeth EF, Fuller F. Molecular cloning and functional expression of human parathyroid
calcium receptor cDNAs. J Biol Chem 270: 12919 12925, 1995.
367. Garrett JE, Tamir H, Kifor O, Simin RT, Rogers KV, Mithal A, Gagel RF, Brown EM.
Calcitonin-secreting cells of the thyroid express an extracellular calcium receptor
gene. Endocrinology 136: 52025211, 1995.
368. Garrick R, Ireland AW, Posen S. Bone abnormalities after gastric surgery. A prospective histological study. Ann Intern Med 75: 221225, 1971.
369. Garuti R, Croce MA, Piccinini L, Tiozzo R, Bertolini S, Calandra S. Functional analysis
of the promoter of human sterol 27-hydroxylase gene in HepG2 cells. Gene 283:
133143, 2002.
370. Gascon-Barre M, Demers C, Ghrab O, Theodoropoulos C, Lapointe R, Jones G,
Valiquette L, Menard D. Expression of CYP27A, a gene encoding a vitamin D-25
hydroxylase in human liver and kidney. Clin Endocrinol 54: 107115, 2001.
351. Fudge NJ, Kovacs CS. Physiological studies in heterozygous calcium sensing receptor
(CaSR) gene-ablated mice confirm that the CaSR regulates calcitonin release in vivo.
BMC Physiol 4: 5, 2004.
371. Geibel J, Sritharan K, Geibel R, Geibel P, Persing JS, Seeger A, Roepke TK, Deichstetter M, Prinz C, Cheng SX, Martin D, Hebert SC. Calcium-sensing receptor
abrogates secretagogue-induced increases in intestinal net fluid secretion by enhancing cyclic nucleotide destruction. Proc Natl Acad Sci USA 103: 9390 9397, 2006.
372. Geibel JP, Hebert SC. The functions and roles of the extracellular Ca2-sensing
receptor along the gastrointestinal tract. Annu Rev Physiol 71: 205217, 2009.
373. Geibel JP, Wagner CA, Caroppo R, Qureshi I, Gloeckner J, Manuelidis L, Kirchhoff P,
Radebold K. The stomach divalent ion-sensing receptor scar is a modulator of gastric
acid secretion. J Biol Chem 276: 39549 39552, 2001.
374. Gerber JG, Payne NA. Secretin inhibits canine gastric acid secretion in response to
pentagastrin by modulating gastric histamine release. J Pharmacol Exp Ther 279:
718 723, 1996.
375. Gerbino A, Ruder WC, Curci S, Pozzan T, Zaccolo M, Hofer AM. Termination of
cAMP signals by Ca2 and Gi via extracellular Ca2 sensors: a link to intracellular
Ca2 oscillations. J Cell Biol 171: 303312, 2005.
376. Gerhard M, Neumayer N, Presecan-Siedel E, Zanner R, Lengyel E, Cramer T,
Hocker M, Prinz C. Gastrin induces expression and promoter activity of the vesicular
monoamine transporter subtype 2. Endocrinology 142: 36633672, 2001.
377. Germain N, Galusca B, Le Roux CW, Bossu C, Ghatei MA, Lang F, Bloom SR, Estour
B. Constitutional thinness and lean anorexia nervosa display opposite concentrations
of peptide YY, glucagon-like peptide 1, ghrelin, and leptin. Am J Clin Nutr 85: 967
971, 2007.
378. Gertner JM, Lilburn M, Domenech M. 25-Hydroxycholecalciferol absorption in steatorrhoea and postgastrectomy osteomalacia. Br Med J 1: 1310 1312, 1977.
379. Gesek FA, Friedman PA. On the mechanism of parathyroid hormone stimulation of
calcium uptake by mouse distal convoluted tubule cells. J Clin Invest 90: 749 758,
1992.
380. Gesty-Palmer D, Chen M, Reiter E, Ahn S, Nelson CD, Wang S, Eckhardt AE, Cowan
CL, Spurney RF, Luttrell LM, Lefkowitz RJ. Distinct beta-arrestin- and G proteindependent pathways for parathyroid hormone receptor-stimulated ERK1/2 activation. J Biol Chem 281: 10856 10864, 2006.
361. Gao XH, Dwivedi PP, Omdahl JL, Morris HA, May BK. Calcitonin stimulates expression of the rat 25-hydroxyvitamin D3-24-hydroxylase (CYP24) promoter in HEK293 cells expressing calcitonin receptor: identification of signaling pathways. J Mol
Endocrinol 32: 8798, 2004.
382. Ghijsen WE, De Jong MD, Van Os CH. Kinetic properties of Na/Ca2 exchange in
basolateral plasma membranes of rat small intestine. Biochim Biophys Acta 730: 85
94, 1983.
363. Garland C, Shekelle RB, Barrett-Connor E, Criqui MH, Rossof AH, Paul O. Dietary
vitamin D and calcium and risk of colorectal cancer: a 19-year prospective study in
men. Lancet 1: 307309, 1985.
247
350. Fu Q, Jilka RL, Manolagas SC, OBrien CA. Parathyroid hormone stimulates receptor
activator of NFkappa B ligand and inhibits osteoprotegerin expression via protein
kinase A activation of cAMP-response element-binding protein. J Biol Chem 277:
48868 48875, 2002.
393. Gray RW, Omdahl JL, Ghazarian JG, DeLuca HF Hydroxycholecalciferol-1-hydroxylase. Subcellular location and properties. J Biol Chem 247: 7528 7532, 1972.
394. Gray SL, Lacroix AZ, Larson J, Robbins J, Cauley JA, Manson JE, Chen Z. Proton
pump inhibitor use, hip fracture, and change in bone mineral density in postmenopausal women: results from the womens health initiative. Arch Internal Med 170:
765771, 2010.
395. Graziani G, Badalamenti S, Como G, Gallieni M, Finazzi S, Angelini C, Brancaccio D,
Ponticelli C. Calcium and phosphate plasma levels in dialysis patients after dietary
Ca-P overload: Role of gastric acid secretion. Nephron 91: 474 479, 2002.
406. Haddad JG, Hillman L, Rojanasathit S. Human serum binding capacity and affinity for
25-hydroxyergocalciferol and 25-hydroxycholecalciferol. J Clin Endocrinol Metab 43:
86 91, 1976.
407. Haddad JG, Jennings AS, Aw TC. Vitamin D uptake and metabolism by perfused rat
liver: influences of carrier proteins. Endocrinology 123: 498 504, 1988.
408. Haddad JG Jr, Walgate J. 25-Hydroxyvitamin D transport in human plasma. Isolation
and partial characterization of calcifidiol-binding protein. J Biol Chem 251: 4803
4809, 1976.
409. Haddad JG Jr, Walgate J. Radioimmunoassay of the binding protein for vitamin D and
its metabolites in human serum: concentrations in normal subjects and patients with
disorders of mineral homeostasis. J Clin Invest 58: 12171222, 1976.
410. Hakanson R, Blom H, Carlsson E, Larsson H, Ryberg B, Sundler F. Hypergastrinaemia produces trophic effects in stomach but not in pancreas and intestines. Regul
Pept 13: 225233, 1986.
411. Hakanson R, Ding XQ, Norlen P, Chen D. Circulating pancreastatin is a marker for
the enterochromaffin-like cells of the rat stomach. Gastroenterology 108: 1445
1452, 1995.
412. Hakanson R, Liedberg G. The role of endogenous gastrin in the activation of gastric
histidine decarboxylase in the rat. Effect of antrectomy and vagal denervation. Eur J
Pharmacol 12: 94 103, 1970.
413. Hakanson R, Owman C. Concomitant histochemical demonstration of histamine
and catecholamines in enterochromaffin-like cells of gastric mucosa. Life Sci 6: 759
766, 1967.
414. Hammer RA, Fernandez C, Ertan A, Arimura A. Anesthetic dependence of the
inhibitory effect of neurotensin on pentagastrin-stimulated acid secretion in rats. A
possible role for somatostatin. Life Sci 48: 333339, 1991.
415. Handlogten ME, Huang C, Shiraishi N, Awata H, Miller RT. The Ca2-sensing receptor activates cytosolic phospholipase A2 via a Gqalpha-dependent ERK-independent pathway. J Biol Chem 276: 1394113948, 2001.
416. Handlogten ME, Shiraishi N, Awata H, Huang C, Miller RT. Extracellular Ca2sensing receptor is a promiscuous divalent cation sensor that responds to lead. Am J
Physiol Renal Physiol 279: F1083F1091, 2000.
417. Hanley DA, Ayer LM. Calcium-dependent release of carboxyl-terminal fragments of
parathyroid hormone by hyperplastic human parathyroid tissue in vitro. J Clin Endocrinol Metab 63: 10751079, 1986.
418. Hanley DA, Takatsuki K, Sultan JM, Schneider AB, Sherwood LM. Direct release of
parathyroid hormone fragments from functioning bovine parathyroid glands in vitro.
J Clin Invest 62: 12471254, 1978.
397. Green T, Dockray GJ. Characterization of the peptidergic afferent innervation of the
stomach in the rat, mouse and guinea-pig. Neuroscience 25: 181193, 1988.
398. Gregory DH, Van Uelft R. Calcium absorption following gastric resection. Am J
Gastroenterol 57: 34 40, 1972.
420. Hansen CP, Goetze JP, Stadil F, Rehfeld JF. Excretion of progastrin products in
human urine. Am J Physiol Gastrointest Liver Physiol 276: G985G992, 1999.
399. Gregory RA, Tracy HJ. The constitution and properties of two gastrins extracted
from hog antral mucosa. Gut 5: 103114, 1964.
421. Hansen KE, Jones AN, Lindstrom MJ, Davis LA, Ziegler TE, Penniston KL, Alvig AL,
Shafer MM. Do proton pump inhibitors decrease calcium absorption? J Bone Miner
Res 25: 2510 2519, 2010.
400. Grisso JA, Kelsey JL, OBrien LA, Miles CG, Sidney S, Maislin G, LaPann K, Moritz D,
Peters B. Risk factors for hip fracture in men. Am J Epidemiol 145: 786 793, 1997.
401. Gunness-Hey M, Hock JM. Increased trabecular bone mass in rats treated with
human synthetic parathyroid hormone. Metab Bone Dis Relat Res 5: 177181, 1984.
402. Guo YD, Strugnell S, Back DW, Jones G. Transfected human liver cytochrome P-450
hydroxylates vitamin D analogs at different side-chain positions. Proc Natl Acad Sci
USA 90: 8668 8672, 1993.
403. Gupta RP, Patrick K, Bell NH. Mutational analysis of CYP27A1: assessment of 27hydroxylation of cholesterol and 25-hydroxylation of vitamin D. Metabolism 56:
1248 1255, 2007.
404. Gyomorey K, Yeger H, Ackerley C, Garami E, Bear CE. Expression of the chloride
channel ClC-2 in the murine small intestine epithelium. Am J Physiol Cell Physiol (could
not determine journal name) 279: 17871794, 2000.
248
422. Hanzlik RP, Fowler SC, Fisher DH. Relative bioavailability of calcium from calcium
formate, calcium citrate, and calcium carbonate. J Pharmacol Exp Ther 313: 1217
1222, 2005.
423. Hardy P, Sechet A, Hottelart C, Oprisiu R, Abighanem O, Said S, Rasombololona M,
Brazier M, Moriniere P, Achard JM, Pruna A, Fournier A. Inhibition of gastric secretion by omeprazole and efficiency of calcium carbonate on the control of hyperphosphatemia in patients on chronic hemodialysis. Artificial Organs 22: 569 573, 1998.
424. Harmeyer J, Deluca HF. Calcium-binding protein and calcium absorption after vitamin D administration. Arch Biochem Biophys 133: 247254, 1969.
425. Hartmann M, Theiss U, Huber R, Luhmann R, Bliesath H, Wurst W, Lucker PW.
Twenty-four-hour intragastric pH profiles and pharmacokinetics following single and
repeated oral administration of the proton pump inhibitor pantoprazole in comparison to omeprazole. Aliment Pharmacol Ther 10: 359 366, 1996.
405. Habener JF, Singer FR, Deftos LJ, Neer RM, Potts JT Jr. Explanation for unusual
potency of salmon calcitonin. Nat New Biol 232: 9192, 1971.
448. Hess AF, Weinstock M. Antirachitic properties imparted to inert fluids by ultraviolet
irradiation. Proc Soc Exp Biol Med 22: 6 7, 1924.
449. Hess AF, Weinstock M. Antirachitic properties imparted to lettuce and to growing
wheat by ultraviolet irradiation. Proc Soc Exp Biol Med 22: 5, 1924.
450. Hess AF, Weinstock M. A further report on imparting antirachitic properties to inert
substances by ultra-violet irradiation. J Biol Chem 63: 297307, 1925.
428. Hattersley G and Chambers TJ. Calcitonin receptors as markers for osteoclastic
differentiation: correlation between generation of bone-resorptive cells and cells
that express calcitonin receptors in mouse bone marrow cultures. Endocrinology
125: 1606 1612, 1989.
451. Hewison M, Burke F, Evans KN, Lammas DA, Sansom DM, Liu P, Modlin RL, Adams
JS. Extra-renal 25-hydroxyvitamin D3-1alpha-hydroxylase in human health and disease. J Steroid Biochem Mol Biol 103: 316 321, 2007.
429. Haussler MR, Myrtle JF, Norman AW. The association of a metabolite of vitamin D3
with intestinal mucosa chromatin in vivo. J Biol Chem 243: 4055 4064, 1968.
452. Hewison M, Freeman L, Hughes SV, Evans KN, Bland R, Eliopoulos AG, Kilby MD,
Moss PA, Chakraverty R. Differential regulation of vitamin D receptor and its ligand
in human monocyte-derived dendritic cells. J Immunol 170: 53825390, 2003.
430. Haussler MR, Norman AW. Chromosomal receptor for a vitamin D metabolite. Proc
Natl Acad Sci USA 62: 155162, 1969.
431. He W, Liu W, Chew CS, Baker SS, Baker RD, Forte JG, Zhu L. Acid secretionassociated translocation of KCNJ15 in gastric parietal cells. Am J Physiol Gastrointest
Liver Physiol 301: G591G600, 2011.
432. Heaney RP, Dowell MS, Bierman J, Hale CA, Bendich A. Absorbability and cost
effectiveness in calcium supplementation. J Am Coll Nutr 20: 239 246, 2001.
433. Heaney RP, Recker RR, Weaver CM. Absorbability of calcium sources: the limited
role of solubility. Calcified Tissue Int 46: 300 304, 1990.
434. Hebert SC, Brown EM, Harris HW. Role of the Ca2-sensing receptor in divalent
mineral ion homeostasis. J Exp Biol 200: 295302, 1997.
454. Heynen G, Brassine A, Daubresse JC, Ligny G, Kanis JA, Gaspar S, Franchimont P.
Lack of clinical and physiological relationship between gastrin and calcitonin in man.
Eur J Clin Invest 11: 331335, 1981.
455. Higham A, Noble P, Thompson DG, Dockray GJ. Increased sensitivity of gastrin cells
to gastric distension following antral denervation in the rat. J Physiol 503: 169 175,
1997.
456. Hildebrand P, Lehmann FS, Ketterer S, Christ AD, Stingelin T, Beltinger J, Gibbons
AH, Coy DH, Calam J, Larsen F, Beglinger C. Regulation of gastric function by
endogenous gastrin releasing peptide in humans: studies with a specific gastrin releasing peptide receptor antagonist. Gut 49: 2328, 2001.
457. Hildmann B, Schmidt A, Murer H. Ca2-transport across basal-lateral plasma membranes from rat small intestinal epithelial cells. J Membr Biol 65: 55 62, 1982.
458. Hill LF, Van den Berg CJ, Mawer EB. Vitamin D metabolism in experimental uraemia:
effects on intestinal transport 45Ca and on formation of 1,25-dihydroxycholecalciferol in rat. Nat New Biol 232: 189 191, 1971.
459. Hills DM, Gerskowitch VP, Roberts SP, Welsh NJ, Shankley NP, Black JW. Pharmacological analysis of the CCKB/gastrin receptors mediating pentagastrin-stimulated
gastric acid secretion in the isolated stomach of the immature rat. Br J Pharmacol 119:
14011410, 1996.
460. Hinata M, Yamamura H, Li L, Watanabe Y, Watano T, Imaizumi Y, Kimura J. Stoichiometry of Na-Ca2 exchange is 3:1 in guinea-pig ventricular myocytes. J Physiol
545: 453 461, 2002.
461. Hirnet D, Olausson J, Fecher-Trost C, Bodding M, Nastainczyk W, Wissenbach U,
Flockerzi V, Freichel M. The TRPV6 gene, cDNA and protein. Cell Calcium 33:
509 518, 2003.
462. Hirsch PF, Baruch H. Is calcitonin an important physiological substance? Endocrine
21: 201208, 2003.
463. Hirsch PF, Gauthier GF, Munson PL. Thyroid hypocalcemic principle and recurrent
laryngeal nerve injury as factors affecting the response to parathyroidectomy in rats.
Endocrinology 73: 244 252, 1963.
464. Hirschfeld J. Immune-electrophoretic demonstration of qualitative differences in
human sera and their relation to the haptoglobins. Acta Pathol Microbiol Scand 47:
160 168, 1959.
465. Hirschfeld J. Individual precipitation patterns of normal rabbit sera. A preliminary
report. Acta Pathol Microbiol Scand 46: 229 238, 1959.
466. Hirschowitz BI, Fong J, Molina E. Effects of pirenzepine and atropine on vagal and
cholinergic gastric secretion and gastrin release and on heart rate in the dog. J
Pharmacol Exp Ther 225: 263268, 1983.
467. Hjalm G, MacLeod RJ, Kifor O, Chattopadhyay N, Brown EM. Filamin-A binds to the
carboxyl-terminal tail of the calcium-sensing receptor, an interaction that participates in CaR-mediated activation of mitogen-activated protein kinase. J Biol Chem
276: 34880 34887, 2001.
468. Hoag HM, Martel J, Gauthier C, Tenenhouse HS. Effects of Npt2 gene ablation and
low-phosphate diet on renal Na/phosphate cotransport and cotransporter gene
expression. J Clin Invest 104: 679 686, 1999.
249
435. Heersche JN, Marcus R, Aurbach GD. Calcitonin and the formation of 3=,5=-AMP in
bone and kidney. Endocrinology 94: 241247, 1974.
453. Hewison M, Zehnder D, Chakraverty R, Adams JS. Vitamin D and barrier function: a
novel role for extra-renal 1 alpha-hydroxylase. Mol Cell Endocrinol 215: 3138, 2004.
droxyvitamin D(3) [1,24-(OH)(2)D(3)], 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] on selected vitamin D-regulated events in the rat. Biochem Pharmacol
60: 701708, 2000.
470. Hocker M, Henihan RJ, Rosewicz S, Riecken EO, Zhang Z, Koh TJ, Wang TC. Gastrin
and phorbol 12-myristate 13-acetate regulate the human histidine decarboxylase
promoter through Raf-dependent activation of extracellular signal-regulated kinaserelated signaling pathways in gastric cancer cells. J Biol Chem 272: 2701527024,
1997.
471. Hocker M, John M, Anagnostopoulos J, Buhr HJ, Solimena M, Gasnier B, Henry JP,
Wang TC, Wiedenmann B. Molecular dissection of regulated secretory pathways in
human gastric enterochromaffin-like cells: an immunohistochemical analysis. Histochem Cell Biol 112: 205214, 1999.
492. Howard A, Legon S, Walters JR. Human and rat intestinal plasma membrane calcium
pump isoforms. Am J Physiol Gastrointest Liver Physiol 265: G917G925, 1993.
472. Hocker M, Zhang Z, Fenstermacher DA, Tagerud S, Chulak M, Joseph D, Wang TC.
Rat histidine decarboxylase promoter is regulated by gastrin through a protein kinase
C pathway. Am J Physiol Gastrointest Liver Physiol 270: G619 G633, 1996.
493. Huan J, Olgaard K, Nielsen LB, Lewin E. Parathyroid hormone 7 84 induces hypocalcemia and inhibits the parathyroid hormone 1 84 secretory response to hypocalcemia in rats with intact parathyroid glands. J Am Soc Nephrol 17: 19231930,
2006.
473. Hoenderop JG, Nilius B, Bindels RJ. Calcium absorption across epithelia. Physiol Rev
85: 373 422, 2005.
474. Hoenderop JG, van der Kemp AW, Hartog A, van de Graaf SF, van Os CH, Willems
PH, Bindels RJ. Molecular identification of the apical Ca2 channel in 1,25-dihydroxyvitamin D3-responsive epithelia. J Biol Chem 274: 8375 8378, 1999.
475. Hoenderop JG, Vennekens R, Muller D, Prenen J, Droogmans G, Bindels RJ, Nilius B.
Function and expression of the epithelial Ca2 channel family: comparison of mammalian ECaC1 and 2. J Physiol 537: 747761, 2001.
495. Huang C, Hujer KM, Wu Z, Miller RT. The Ca2-sensing receptor couples to
G12/13 to activate phospholipase D in Madin-Darby canine kidney cells. Am J Physiol
Cell Physiol 286: C22C30, 2004.
496. Huang C, Wu Z, Hujer KM, Miller RT. Silencing of filamin A gene expression inhibits
Ca2-sensing receptor signaling. FEBS Lett 580: 17951800, 2006.
497. Huang JC, Sakata T, Pfleger LL, Bencsik M, Halloran BP, Bikle DD, Nissenson RA.
PTH differentially regulates expression of RANKL and OPG. J Bone Miner Res 19:
235244, 2004.
498. Huang Y, Niwa J, Sobue G, Breitwieser GE. Calcium-sensing receptor ubiquitination
and degradation mediated by the E3 ubiquitin ligase dorfin. J Biol Chem 281: 11610
11617, 2006.
499. Huang Y, Zhou Y, Castiblanco A, Yang W, Brown EM, Yang JJ. Multiple Ca2-binding
sites in the extracellular domain of the Ca2-sensing receptor corresponding to
cooperative Ca2 response. Biochemistry 48: 388 398, 2009.
500. Huang Y, Zhou Y, Yang W, Butters R, Lee HW, Li S, Castiblanco A, Brown EM, Yang
JJ. Identification and dissection of Ca2-binding sites in the extracellular domain of
Ca2-sensing receptor. J Biol Chem 282: 19000 19010, 2007.
501. Huda MS, Durham BH, Wong SP, Dovey TM, McCulloch P, Kerrigan D, Pinkney JH,
Fraser WD, Wilding JP. Lack of an acute effect of ghrelin on markers of bone
turnover in healthy controls and post-gastrectomy subjects. Bone 41: 406 413,
2007.
502. Hughes DA, Tang K, Strotmann R, Schoneberg T, Prenen J, Nilius B, Stoneking M.
Parallel selection on TRPV6 in human populations. PLoS ONE 3: e1686, 2008.
503. Huhtakangas JA, Olivera CJ, Bishop JE, Zanello LP, Norman AW. The vitamin D
receptor is present in caveolae-enriched plasma membranes and binds 1
alpha,25(OH)2-vitamin D3 in vivo and in vitro. Mol Endocrinol 18: 2660 2671, 2004.
504. Huldschinsky K. Heilung von Rachitis durch knstliche Hhensonne. Deutsche Med
Wochenschrift 45: 712, 1919.
485. Holst MC, Kelly JB, Powley TL. Vagal preganglionic projections to the enteric nervous system characterized with Phaseolus vulgaris-leucoagglutinin. J Comp Neurol
381: 81100, 1997.
505. Hume EM, Smith HH. The effect of irradiation of the environment with ultra-violet
light upon the growth and calcification of rats, fed on a diet deficient in fat-soluble
vitamins: the part played by irradiated sawdust. Biochem J 18: 1334 1345, 1924.
486. Holst Pedersen J, Skov Olsen P, Kirkegaard P. Effect of neurotensin and neurotensin
fragments on gastric acid secretion in man. Regul Pept 15: 77 86, 1986.
506. Humphries TJ, Merritt GJ. Review article: drug interactions with agents used to treat
acid-related diseases. Aliment Pharmacol Ther 13 Suppl 3: 18 26, 1999.
487. Holtrop ME, Raisz LG, Simmons HA. The effects of parathyroid hormone, colchicine, and calcitonin on the ultrastructure and the activity of osteoclasts in organ
culture. J Cell Biol 60: 346 355, 1974.
508. Ichikawa F, Sato K, Nanjo M, Nishii Y, Shinki T, Takahashi N, Suda T. Mouse primary
osteoblasts express vitamin D3 25-hydroxylase mRNA and convert 1 alpha-hydroxyvitamin D3 into 1 alpha,25-dihydroxyvitamin D3. Bone 16: 129 135, 1995.
509. Imai M. Calcium transport across the rabbit thick ascending limb of Henles loop
perfused in vitro. Pflgers Arch 374: 255263, 1978.
250
476. Hoenderop JG, Voets T, Hoefs S, Weidema F, Prenen J, Nilius B, Bindels RJ. Homoand heterotetrameric architecture of the epithelial Ca2 channels TRPV5 and
TRPV6. EMBO J 22: 776 785, 2003.
494. Huang C, Handlogten ME, Miller RT. Parallel activation of phosphatidylinositol 4-kinase and phospholipase C by the extracellular calcium-sensing receptor. J Biol Chem
277: 2029320300, 2002.
531. Jilka RL, Weinstein RS, Bellido T, Roberson P, Parfitt AM, Manolagas SC. Increased
bone formation by prevention of osteoblast apoptosis with parathyroid hormone. J
Clin Invest 104: 439 446, 1999.
532. Jin HO, Lee KY, Chang TM, Chey WY, Dubois A. Secretin: a physiological regulator
of gastric emptying and acid output in dogs. Am J Physiol Gastrointest Liver Physiol 267:
G702G708, 1994.
533. Johnson JA, Grande JP, Roche PC, Kumar R. Ontogeny of the 1,25-dihydroxyvitamin
D3 receptor in fetal rat bone. J Bone Miner Res 11: 56 61, 1996.
534. Johnson LR, Lichtenberger LM, Copeland EM, Dudrick SJ, Castro GA. Action of
gastrin on gastrointestinal structure and function. Gastroenterology 68: 1184 1192,
1975.
535. Jones B, Jones EL, Bonney SA, Patel HN, Mensenkamp AR, Eichenbaum-Voline S,
Rudling M, Myrdal U, Annesi G, Naik S, Meadows N, Quattrone A, Islam SA, Naoumova RP, Angelin B, Infante R, Levy E, Roy CC, Freemont PS, Scott J, Shoulders CC.
Mutations in a Sar1 GTPase of COPII vesicles are associated with lipid absorption
disorders. Nat Genet 34: 29 31, 2003.
536. Juppner H, Abou-Samra AB, Freeman M, Kong XF, Schipani E, Richards J, Kolakowski LF Jr, Hock J, Potts JT Jr, Kronenberg HM. A G protein-linked receptor for
parathyroid hormone and parathyroid hormone-related peptide. Science 254:
1024 1026, 1991.
537. Jurutka PW, Thompson PD, Whitfield GK, Eichhorst KR, Hall N, Dominguez CE,
Hsieh JC, Haussler CA, Haussler MR. Molecular and functional comparison of 1,25dihydroxyvitamin D3 and the novel vitamin D receptor ligand, lithocholic acid, in
activating transcription of cytochrome P450 3A4. J Cell Biochem 94: 917943, 2005.
538. Juttmann JR, Visser TJ, Buurman C, de Kam E, Birkenhager JC. Seasonal fluctuations
in serum concentrations of vitamin D metabolites in normal subjects. Br Med J 282:
1349 1352, 1981.
539. Kahrilas PJ, Dent J, Lauritsen K, Malfertheiner P, Denison H, Franzen S, Hasselgren
G. A randomized, comparative study of three doses of AZD0865 and esomeprazole
for healing of reflux esophagitis. Clin Gastroenterol Hepatol 5: 13851391, 2007.
540. Kajikawa M, Ishida H, Fujimoto S, Mukai E, Nishimura M, Fujita J, Tsuura Y, Okamoto
Y, Norman AW, Seino Y. An insulinotropic effect of vitamin D analog with increasing
intracellular Ca2 concentration in pancreatic beta-cells through nongenomic signal
transduction. Endocrinology 140: 4706 4712, 1999.
541. Kajimura M, Reuben MA, Sachs G. The muscarinic receptor gene expressed in rabbit
parietal cells is the m3 subtype. Gastroenterology 103: 870 875, 1992.
523. Jain RN, Samuelson LC. Transcriptional profiling of gastrin-regulated genes in mouse
stomach. Physiol Genomics 29: 112, 2007.
526. Jeffery DA, Roufogalis BD, Katz S. The effect of calmodulin on the phosphoprotein
intermediate of Mg2-dependent Ca2-stimulated adenosine triphosphatase in human erythrocyte membranes. Biochem J 194: 481 486, 1981.
527. Jeffery PL, McGuckin MA, Linden SK. Endocrine impact of Helicobacter pylori: focus
on ghrelin and ghrelin o-acyltransferase. World J Gastroenterol 17: 1249 1260, 2011.
528. Jeon TY, Lee S, Kim HH, Kim YJ, Son HC, Kim DH, Sim MS. Changes in plasma
ghrelin concentration immediately after gastrectomy in patients with early gastric
cancer. J Clin Endocrinol Metab 89: 53925396, 2004.
529. Jiang Y, Minet E, Zhang Z, Silver PA, Bai M. Modulation of interprotomer relationships is important for activation of dimeric calcium-sensing receptor. J Biol Chem 279:
1414714156, 2004.
545. Karam SM, Straiton T, Hassan WM, Leblond CP. Defining epithelial cell progenitors
in the human oxyntic mucosa. Stem Cells 21: 322336, 2003.
546. Karaplis AC, Lim SK, Baba H, Arnold A, Kronenberg HM. Inefficient membrane
targeting, translocation, and proteolytic processing by signal peptidase of a mutant
preproparathyroid hormone protein. J Biol Chem 270: 1629 1635, 1995.
547. Karp HJ, Ketola ME, Lamberg-Allardt CJ. Acute effects of calcium carbonate, calcium
citrate and potassium citrate on markers of calcium and bone metabolism in young
women. Br J Nutr 102: 13411347, 2009.
548. Karvar S, Yao X, Crothers JM Jr, Liu Y, Forte JG. Localization and function of soluble
N-ethylmaleimide-sensitive factor attachment protein-25 and vesicle-associated
251
530. Jilka RL, OBrien CA, Ali AA, Roberson PK, Weinstein RS, Manolagas SC. Intermittent PTH stimulates periosteal bone formation by actions on post-mitotic preosteoblasts. Bone 44: 275286, 2009.
557. Kawakami M, Blum CB, Ramakrishnan R, Dell RB, Goodman DS. Turnover of the
plasma binding protein for vitamin D and its metabolites in normal human subjects.
J Clin Endocrinol Metab 53: 1110 1116, 1981.
558. Kawashima K, Ishihara S, Karim Rumi MA, Moriyama N, Kazumori H, Suetsugu H,
Sato H, Fukuda R, Adachi K, Shibata M, Onodera S, Chiba T, Kinoshita Y. Localization
of calcitonin gene-related peptide receptors in rat gastric mucosa. Peptides 23: 955
966, 2002.
559. Kaye JA, Jick H. Proton pump inhibitor use and risk of hip fractures in patients
without major risk factors. Pharmacotherapy 28: 951959, 2008.
560. Kazumori H, Ishihara S, Kawashima K, Fukuda R, Chiba T, Kinoshita Y. Analysis of
gastrin receptor gene expression in proliferating cells in the neck zone of gastric
fundic glands using laser capture microdissection. FEBS Lett 489: 208 214, 2001.
561. Keeley TM, Samuelson LC. Cytodifferentiation of the postnatal mouse stomach in
normal and Huntingtin-interacting protein 1-related-deficient mice. Am J Physiol Gastrointest Liver Physiol 299: G1241G1251, 2010.
562. Keeton TP, Burk SE, Shull GE. Alternative splicing of exons encoding the calmodulinbinding domains and C termini of plasma membrane Ca2-ATPase isoforms 1, 2, 3,
and 4. J Biol Chem 268: 2740 2748, 1993.
563. Kehayoglou AK, Holdsworth CD, Agnew JE, Whelton MJ, Sherlock S. Bone disease
and calcium absorption in primary biliary cirrhosis with special reference to vitamin-D therapy. Lancet 1: 715718, 1968.
564. Keinke O, Ehrlein HJ, Wulschke S. Mechanical factors regulating gastric emptying
examined by the effects of exogenous cholecystokinin and secretin on canine gastroduodenal motility. Can J Physiol Pharmacol 65: 287292, 1987.
565. Kemper B, Habener JF, Mulligan RC, Potts JT Jr, Rich A. Pre-proparathyroid hormone: a direct translation product of parathyroid messenger RNA. Proc Natl Acad Sci
USA 71: 37313735, 1974.
569. Kidd M, Hauso O, Drozdov I, Gustafsson BI, Modlin IM. Delineation of the chemomechanosensory regulation of gastrin secretion using pure rodent G cells. Gastroenterology 137: 231241, 2009.
570. Kidd M, Modlin IM, Black JW, Boyce M, Culler M. A comparison of the effects of
gastrin, somatostatin and dopamine receptor ligands on rat gastric enterochromaffin-like cell secretion and proliferation. Regul Pept 143: 109 117, 2007.
571. Kifor O, Diaz R, Butters R, Kifor I, Brown EM. The calcium-sensing receptor is
localized in caveolin-rich plasma membrane domains of bovine parathyroid cells. J
Biol Chem 273: 21708 21713, 1998.
572. Kifor O, MacLeod RJ, Diaz R, Bai M, Yamaguchi T, Yao T, Kifor I, Brown EM.
Regulation of MAP kinase by calcium-sensing receptor in bovine parathyroid and
CaR-transfected HEK293 cells. Am J Physiol Renal Physiol 280: F291F302, 2001.
573. Kikuchi K, Kikuchi T, Ghishan FK. Characterization of calcium transport by basolateral membrane vesicles of human small intestine. Am J Physiol Gastrointest Liver
Physiol 255: G482G489, 1988.
574. Kim HJ, Yang DK, So I. PDZ domain-containing protein as a physiological modulator
of TRPV6. Biochem Biophys Res Commun 361: 433 438, 2007.
575. Kim MS, Fujiki R, Murayama A, Kitagawa H, Yamaoka K, Yamamoto Y, Mihara M,
Takeyama K, Kato S. 1Alpha,25(OH)2D3-induced transrepression by vitamin D receptor through E-box-type elements in the human parathyroid hormone gene promoter. Mol Endocrinol 21: 334 342, 2007.
576. Kim SW, Her SJ, Park SJ, Kim D, Park KS, Lee HK, Han BH, Kim MS, Shin CS, Kim SY.
Ghrelin stimulates proliferation and differentiation and inhibits apoptosis in osteoblastic MC3T3-E1 cells. Bone 37: 359 369, 2005.
577. Kirchhoff P, Andersson K, Socrates T, Sidani S, Kosiek O, Geibel JP. Characteristics
of the K-competitive H,K-ATPase inhibitor AZD0865 in isolated rat gastric
glands. Am J Physiol Gastrointest Liver Physiol 291: G838 G843, 2006.
578. Kirton CM, Wang T, Dockray GJ. Regulation of parietal cell migration by gastrin in
the mouse. Am J Physiol Gastrointest Liver Physiol 283: G787G793, 2002.
579. Klenk C, Schulz S, Calebiro D, Lohse MJ. Agonist-regulated cleavage of the extracellular domain of parathyroid hormone receptor type 1. J Biol Chem 285: 8665
8674, 2010.
580. Klenk C, Vetter T, Zurn A, Vilardaga JP, Friedman PA, Wang B, Lohse MJ. Formation
of a ternary complex among NHERF1, beta-arrestin, parathyroid hormone receptor. J Biol Chem 285: 3035530362, 2010.
581. Klotz U. Pharmacokinetic considerations in the eradication of Helicobacter pylori.
Clin Pharmacokinet 38: 243270, 2000.
582. Klotz U, Schwab M, Treiber G. CYP2C19 polymorphism and proton pump inhibitors. Basic Clin Pharmacol Toxicol 95: 2 8, 2004.
583. Ko SH, Choi KC, Oh GT, Jeung EB. Effect of dietary calcium and 1,25-(OH)2D3 on
the expression of calcium transport genes in calbindin-D9k and -D28k double knockout mice. Biochem Biophys Res Commun 379: 227232, 2009.
584. Kobayashi T, Tonai S, Ishihara Y, Koga R, Okabe S, Watanabe T. Abnormal functional
and morphological regulation of the gastric mucosa in histamine H2 receptor-deficient mice. J Clin Invest 105: 17411749, 2000.
585. Kocian J, Brodan V. New observations on the absorption of 47Ca in patients with
partial gastrectomy. Digestion 12: 193200, 1975.
586. Kodicek E, Lawson DE, Wilson PW. Biological activity of a polar metabolite of
vitamin D. Nature 228: 763764, 1970.
566. Keusch I, Traebert M, Lotscher M, Kaissling B, Murer H, Biber J. Parathyroid hormone and dietary phosphate provoke a lysosomal routing of the proximal tubular
Na/Pi-cotransporter type II. Kidney Int 54: 1224 1232, 1998.
587. Koh TJ, Field JK, Varro A, Liloglou T, Fielding P, Cui G, Houghton J, Dockray GJ,
Wang TC. Glycine-extended gastrin promotes the growth of lung cancer. Cancer Res
64: 196 201, 2004.
252
568. Khanal RC, Peters TM, Smith NM, Nemere I. Membrane receptor-initiated signaling
in 1,25(OH)2D3-stimulated calcium uptake in intestinal epithelial cells. J Cell Biochem
105: 1109 1116, 2008.
597. Kopp R, Pfeiffer A. Effects of phorbol ester treatment on dibutyryl cyclic adenosine-5= monophosphate- and carbachol-stimulated aminopyrine accumulation in isolated rat parietal cells. Scand J Gastroenterol 35: 686 693, 2000.
598. Kos CH, Karaplis AC, Peng JB, Hediger MA, Goltzman D, Mohammad KS, Guise TA,
Pollak MR. The calcium-sensing receptor is required for normal calcium homeostasis
independent of parathyroid hormone. J Clin Invest 111: 10211028, 2003.
599. Koshihara Y, Hoshi K, Ishibashi H, Shiraki M. Vitamin K2 promotes 1alpha,25(OH)2
vitamin D3-induced mineralization in human periosteal osteoblasts. Calcif Tissue Int
59: 466 473, 1996.
600. Koushik SV, Wang J, Rogers R, Moskophidis D, Lambert NA, Creazzo TL, Conway
SJ. Targeted inactivation of the sodium-calcium exchanger (Ncx1) results in the lack
of a heartbeat and abnormal myofibrillar organization. FASEB J 15: 1209 1211, 2001.
601. Kozoni V, Tsioulias G, Shiff S, Rigas B. The effect of lithocholic acid on proliferation
and apoptosis during the early stages of colon carcinogenesis: differential effect on
apoptosis in the presence of a colon carcinogen. Carcinogenesis 21: 999 1005, 2000.
602. Kretsinger RH, Mann JE, Simmonds JG. Model of facilitated diffusion of calcium by
the intestinal calcium-binding protein. In: Proceedings of the Fifth Workshop on Vitamin
D, edited by Norman AW, Schaefer K, Herrath DV, Grigoleit HG. Berlin: Debruyter,
1982, p. 232248.
603. Kreutz M, Andreesen R, Krause SW, Szabo A, Ritz E, Reichel H. 1,25-Dihydroxyvitamin D3 production and vitamin D3 receptor expression are developmentally regulated during differentiation of human monocytes into macrophages. Blood 82:
1300 1307, 1993.
604. Krisinger J, Strom M, Darwish HD, Perlman K, Smith C, DeLuca HF. Induction of
calbindin-D 9k mRNA but not calcium transport in rat intestine by 1,25-dihydroxyvitamin D3 24-homologs. J Biol Chem 266: 1910 1913, 1991.
605. Kubler N, Krause U, Wagner PK, Beyer J, Rothmund M. The secretion of parathyroid
hormone and its fragments from dispersed cells of adenomatous parathyroid tissue
at different calcium concentrations. Exp Clin Endocrinol 88: 101108, 1986.
606. Kuestner RE, Elrod RD, Grant FJ, Hagen FS, Kuijper JL, Matthewes SL, OHara PJ,
Sheppard PO, Stroop SD, Thompson DL. Cloning and characterization of an abundant subtype of the human calcitonin receptor. Mol Pharmacol 46: 246 255, 1994.
607. Kuhn B, Schmid A, Harteneck C, Gudermann T, Schultz G. G proteins of the Gq
family couple the H2 histamine receptor to phospholipase C. Mol Endocrinol 10:
16971707, 1996.
609. Kumar R, Cohen WR, Silva P, Epstein FH. Elevated 1,25-dihydroxyvitamin D plasma
levels in normal human pregnancy and lactation. J Clin Invest 63: 342344, 1979.
610. Kumar R, Schaefer J, Grande JP, Roche PC. Immunolocalization of calcitriol receptor,
24-hydroxylase cytochrome P-450, and calbindin D28k in human kidney. Am J Physiol
Renal Fluid Electrolyte Physiol 266: F477F485, 1994.
611. Kunishima N, Shimada Y, Tsuji Y, Sato T, Yamamoto M, Kumasaka T, Nakanishi S,
Jingami H, Morikawa K. Structural basis of glutamate recognition by a dimeric
metabotropic glutamate receptor. Nature 407: 971977, 2000.
612. Kuro-o M, Matsumura Y, Aizawa H, Kawaguchi H, Suga T, Utsugi T, Ohyama Y,
Kurabayashi M, Kaname T, Kume E, Iwasaki H, Iida A, Shiraki-Iida T, Nishikawa S,
Nagai R, Nabeshima YI. Mutation of the mouse klotho gene leads to a syndrome
resembling ageing. Nature 390: 4551, 1997.
613. Kutuzova GD, Akhter S, Christakos S, Vanhooke J, Kimmel-Jehan C, DeLuca HF.
Calbindin D9k knockout mice are indistinguishable from wild-type mice in phenotype and serum calcium level. Proc Natl Acad Sci USA 103: 1237712381, 2006.
614. Kutuzova GD, Deluca HF. Gene expression profiles in rat intestine identify pathways
for 1,25-dihydroxyvitamin D3 stimulated calcium absorption and clarify its immunomodulatory properties. Arch Biochem Biophys 432: 152166, 2004.
615. Kutuzova GD, Sundersingh F, Vaughan J, Tadi BP, Ansay SE, Christakos S, Deluca
HF. TRPV6 is not required for 1alpha,25-dihydroxyvitamin D3-induced intestinal
calcium absorption in vivo. Proc Natl Acad Sci USA 105: 1965519659, 2008.
616. Kwok CS, Yeong JK, Loke YK. Meta-analysis: risk of fractures with acid-suppressing
medication. Bone 48: 768 776, 2011.
617. Labuda M, Labuda D, Korab-Laskowska M, Cole DE, Zietkiewicz E, Weissenbach J,
Popowska E, Pronicka E, Root AW, Glorieux FH. Linkage disequilibrium analysis in
young populations: pseudo-vitamin D-deficiency rickets and the founder effect in
French Canadians. Am J Hum Genet 59: 633 643, 1996.
618. Labuda M, Morgan K, Glorieux FH. Mapping autosomal recessive vitamin D dependency type I to chromosome 12q14 by linkage analysis. Am J Hum Genet 47: 28 36,
1990.
619. Lambers TT, Weidema AF, Nilius B, Hoenderop JG, Bindels RJ. Regulation of the
mouse epithelial Ca2 channel TRPV6 by the Ca2-sensor calmodulin. J Biol Chem
279: 2885528861, 2004.
620. Lamberts R, Stumps D, Plumpe L, Creutzfeldt W. Somatostatin cells in rat antral
mucosa: qualitative and quantitative ultrastructural analyses in different states of
gastric acid secretion. Histochemistry 95: 373382, 1991.
621. Lane NE, Sanchez S, Modin GW, Genant HK, Pierini E, Arnaud CD. Parathyroid
hormone treatment can reverse corticosteroid-induced osteoporosis. Results of a
randomized controlled clinical trial. J Clin Invest 102: 16271633, 1998.
622. Langhans N, Rindi G, Chiu M, Rehfeld JF, Ardman B, Beinborn M, Kopin AS. Abnormal gastric histology and decreased acid production in cholecystokinin-B/gastrin
receptor-deficient mice. Gastroenterology 112: 280 286, 1997.
623. Langub MC, Reinhardt TA, Horst RL, Malluche HH, Koszewski NJ. Characterization
of vitamin D receptor immunoreactivity in human bone cells. Bone 27: 383387,
2000.
624. Lapierre LA, Avant KM, Caldwell CM, Ham AJ, Hill S, Williams JA, Smolka AJ,
Goldenring JR. Characterization of immunoisolated human gastric parietal cells tubulovesicles: identification of regulators of apical recycling. Am J Physiol Gastrointest
Liver Physiol 292: G1249 G1262, 2007.
625. Lark RK, Lester GE, Ontjes DA, Blackwood AD, Hollis BW, Hensler MM, Aris RM.
Diminished and erratic absorption of ergocalciferol in adult cystic fibrosis patients.
Am J Clin Nutr 73: 602 606, 2001.
626. Larsen EH, Nedergaard S, Ussing HH. Role of lateral intercellular space and sodium
recirculation for isotonic transport in leaky epithelia. Rev Physiol Biochem Pharmacol
141: 153212, 2000.
627. Larsen FL, Katz S, Roufogalis BD. Calmodulin regulation of Ca2 transport in human
erythrocytes. Biochem J 200: 185191, 1981.
253
596. Kopin AS, Lee YM, McBride EW, Miller LJ, Lu M, Lin HY, Kolakowski LF Jr, Beinborn
M. Expression cloning and characterization of the canine parietal cell gastrin receptor. Proc Natl Acad Sci USA 89: 36053609, 1992.
649. Lepard KJ, Chi J, Mohammed JR, Gidener S, Stephens RL Jr. Gastric antisecretory
effect of serotonin: quantitation of release and site of action. Am J Physiol Endocrinol
Metab 271: E669 E677, 1996.
650. LePard KJ, Stephens RL Jr. Serotonin inhibits gastric acid secretion through a 5-hydroxytryptamine1-like receptor in the rat. J Pharmacol Exp Ther 270: 1139 1144,
1994.
630. Larsson B, Norlen P, Lindstrom E, Zhao D, Hakanson R, Linde A. Effects of ECL cell
extracts and granule/vesicle-enriched fractions from rat oxyntic mucosa on cAMP
and IP3 in rat osteoblast-like cells. Regul Pept 106: 1318, 2002.
651. Leth RD, Abrahamsson H, Kilander A, Lundell LR. Malabsorption of fat after partial
gastric resection. A study of pathophysiologic mechanisms. Eur J Surg 157: 205208,
1991.
631. Larsson H, Carlsson E, Ryberg B, Fryklund J, Wallmark B. Rat parietal cell function
after prolonged inhibition of gastric acid secretion. Am J Physiol Gastrointest Liver
Physiol 254: G33G39, 1988.
652. Levant JA, Walsh JH, Isenberg JI. Stimulation of gastric secretion and gastrin release
by single oral doses of calcium carbonate in man. N Engl J Med 289: 555558, 1973.
632. Larsson LI, Goltermann N, de Magistris L, Rehfeld JF, Schwartz TW. Somatostatin
cell processes as pathways for paracrine secretion. Science 205: 13931395, 1979.
633. Lawson DE, Fraser DR, Kodicek E, Morris HR, Williams DH. Identification of 1,25dihydroxycholecalciferol, a new kidney hormone controlling calcium metabolism.
Nature 230: 228 230, 1971.
635. Lawton DE, Simcock DC, Candy EJ, Simpson HV. Gastrin secretion by ovine antral
mucosa in vitro. Comp Biochem Physiol A Mol Integr Physiol 126: 233243, 2000.
655. Lewis JJ, Zdon MJ, Adrian TE, Modlin IM. Pancreastatin: a novel peptide inhibitor of
parietal cell secretion. Surgery 104: 10311036, 1988.
636. Lawton GP, Tang LH, Miu K, Gilligan CJ, Absood A, Modlin IM. Adrenergic and
cromolyn sodium modulation of ECL cell histamine secretion. J Surg Res 58: 96 104,
1995.
656. Li P, Chang TM, Chey WY. Secretin inhibits gastric acid secretion via a vagal afferent
pathway in rats. Am J Physiol Gastrointest Liver Physiol 275: G22G28, 1998.
637. Le Moullec JM, Jullienne A, Chenais J, Lasmoles F, Guliana JM, Milhaud G, Moukhtar
MS. The complete sequence of human preprocalcitonin. FEBS Lett 167: 9397, 1984.
657. Li P, Chang TM, Coy D, Chey WY. Inhibition of gastric acid secretion in rat stomach
by PACAP is mediated by secretin, somatostatin, and PGE2. Am J Physiol Gastrointest
Liver Physiol 278: G121G127, 2000.
638. Leclerc R, Pelletier G, Puviani R, Arimura A, Schally AV. Immunohistochemical localization of somatostatin in endocrine cells of the rat stomach. Mol Cell Endocrinol 4:
257261, 1976.
639. Lee GS, Lee KY, Choi KC, Ryu YH, Paik SG, Oh GT, Jeung EB. Phenotype of a
calbindin-D9k gene knockout is compensated for by the induction of other calcium
transporter genes in a mouse model. J Bone Miner Res 22: 1968 1978, 2007.
640. Lee JW, Fuda H, Javitt NB, Strott CA, Rodriguez IR. Expression and localization of
sterol 27-hydroxylase (CYP27A1) in monkey retina. Exp Eye Res 83: 465 469, 2006.
641. Lee MP, Ravenel JD, Hu RJ, Lustig LR, Tomaselli G, Berger RD, Brandenburg SA, Litzi
TJ, Bunton TE, Limb C, Francis H, Gorelikow M, Gu H, Washington K, Argani P,
Goldenring JR, Coffey RJ, Feinberg AP. Targeted disruption of the Kvlqt1 gene
causes deafness and gastric hyperplasia in mice. J Clin Invest 106: 14471455, 2000.
642. Lefkowitz ES, Garland CF. Sunlight, vitamin D, and ovarian cancer mortality rates in
US women. Int J Epidemiol 23: 11331136, 1994.
643. Leheste JR, Melsen F, Wellner M, Jansen P, Schlichting U, Renner-Muller I, Andreassen TT, Wolf E, Bachmann S, Nykjaer A, Willnow TE. Hypocalcemia and osteopathy in mice with kidney-specific megalin gene defect. FASEB J 17: 247249, 2003.
644. Lehto-Axtelius D, Chen D, Surve VV, Hakanson R. Post-gastrectomy osteopenia in
the rat: bone structure is preserved by retaining 10%-30% of the oxyntic gland area.
Scand J Gastroenterol 37: 437 443, 2002.
645. Leichtmann GA, Bengoa JM, Bolt MJ, Sitrin MD. Intestinal absorption of cholecalciferol and 25-hydroxycholecalciferol in patients with both Crohns disease and intestinal resection. Am J Clin Nutr 54: 548 552, 1991.
646. Leitersdorf E, Reshef A, Meiner V, Levitzki R, Schwartz SP, Dann EJ, Berkman N, Cali
JJ, Klapholz L, Berginer VM. Frameshift and splice-junction mutations in the sterol
27-hydroxylase gene cause cerebrotendinous xanthomatosis in Jews or Moroccan
origin. J Clin Invest 91: 2488 2496, 1993.
647. Lemay J, Demers C, Hendy GN, Gascon-Barr M. Oral calcium transiently increases
calbindin(9k) gene expression in adult rat duodena. Calcified Tissue Int 60: 43 47,
1997.
648. Lepage R, Roy L, Brossard JH, Rousseau L, Dorais C, Lazure C, DAmour P. A
non-(1 84) circulating parathyroid hormone (PTH) fragment interferes significantly
with intact PTH commercial assay measurements in uremic samples. Clin Chem 44:
805 809, 1998.
254
658. Li XF, Kraev AS, Lytton J. Molecular cloning of a fourth member of the potassiumdependent sodium-calcium exchanger gene family, NCKX4. J Biol Chem 277:
48410 48417, 2002.
659. Li Y, Wu X, Yao H, Owyang C. Secretin activates vagal primary afferent neurons in
the rat: evidence from electrophysiological and immunohistochemical studies. Am J
Physiol Gastrointest Liver Physiol 289: G745G752, 2005.
660. Li YC. Vitamin D regulation of the renin-angiotensin system. J Cell Biochem 88:
327331, 2003.
661. Li YC, Amling M, Pirro AE, Priemel M, Meuse J, Baron R, Delling G, Demay MB.
Normalization of mineral ion homeostasis by dietary means prevents hyperparathyroidism, rickets, osteomalacia, but not alopecia in vitamin D receptor-ablated mice.
Endocrinology 139: 4391 4396, 1998.
662. Li YC, Kong J, Wei M, Chen ZF, Liu SQ, Cao LP. 1,25-Dihydroxyvitamin D3 is a
negative endocrine regulator of the renin-angiotensin system. J Clin Invest 110: 229
238, 2002.
663. Li YC, Pirro AE, Demay MB. Analysis of vitamin D-dependent calcium-binding protein messenger ribonucleic acid expression in mice lacking the vitamin D receptor.
Endocrinology 139: 847 851, 1998.
664. Li YY. Mechanisms for regulation of gastrin and somatostatin release from isolated
rat stomach during gastric distention. World J Gastroenterol 9: 129 133, 2003.
665. Lian J, Stewart C, Puchacz E, Mackowiak S, Shalhoub V, Collart D, Zambetti G, Stein
G. Structure of the rat osteocalcin gene and regulation of vitamin D-dependent
expression. Proc Natl Acad Sci USA 86: 11431147, 1989.
666. Lieben L, Benn BS, Ajibade D, Stockmans I, Moermans K, Hediger MA, Peng JB,
Christakos S, Bouillon R, Carmeliet G. Trpv6 mediates intestinal calcium absorption
during calcium restriction and contributes to bone homeostasis. Bone 47: 301308,
2010.
667. Liedman B, Bosaeus I, Mellstrom D, Lundell L. Osteoporosis after total gastrectomy.
Results of a prospective, clinical study. Scand J Gastroenterol 32: 1090 1095, 1997.
668. Liedman B, Henningsson A, Mellstrom D, Lundell L. Changes in bone metabolism
and body composition after total gastrectomy: results of a longitudinal study. Dig Dis
Sci 45: 819 824, 2000.
634. Lawson DE, Wilson PW, Kodicek E. New vitamin D metabolite localized in intestinal
cell nuclei. Nature 222: 171172, 1969.
689. Ma YL, Cain RL, Halladay DL, Yang X, Zeng Q, Miles RR, Chandrasekhar S, Martin
TJ, Onyia JE. Catabolic effects of continuous human PTH (138) in vivo is associated
with sustained stimulation of RANKL and inhibition of osteoprotegerin and geneassociated bone formation. Endocrinology 142: 4047 4054, 2001.
690. MacCallum WG, Voegtlin C. On the regulation of the parathyroid to calcium metabolism and the nature of tetany. Bull Johns Hopkins Hosp 19: 91, 1908.
691. Maccarinelli G, Sibilia V, Torsello A, Raimondo F, Pitto M, Giustina A, Netti C, Cocchi
D. Ghrelin regulates proliferation and differentiation of osteoblastic cells. J Endocrinol
184: 249 256, 2005.
692. Mace OJ, Morgan EL, Affleck JA, Lister N, Kellett GL. Calcium absorption by Cav1.3
induces terminal web myosin II phosphorylation and apical GLUT2 insertion in rat
intestine. J Physiol 580: 605 616, 2007.
693. MacGregor RR, Cohn DV, Hamilton JW. The content of carboxyl-terminal fragments of parathormone in extracts of fresh bovine parathyroids. Endocrinology 112:
1019 1025, 1983.
694. Madaus S, Bender H, Schusdziarra V, Kehe K, Munzert G, Weber G, Classen M.
Vagally induced release of gastrin, somatostatin and bombesin-like immunoreactivity
from perfused rat stomach. Effect of stimulation frequency and cholinergic mechanisms. Regul Pept 30: 179 192, 1990.
676. Liu C, Chen J, Guo Y, Yang L, Zhao C, Bai L. The expression of PTHLH in human
gastric mucosa enterochromaffin-like cells. Dig Dis Sci 56: 993998, 2011.
696. Madhok TC, DeLuca HF. Characteristics of the rat liver microsomal enzyme system
converting cholecalciferol into 25-hydroxycholecalciferol. Evidence for the participation of cytochrome p-450. Biochem J 184: 491 499, 1979.
677. Lloyd KC, Amirmoazzami S, Friedik F, Heynio A, Solomon TE, Walsh JH. Candidate
canine enterogastrones: acid inhibition before and after vagotomy. Am J Physiol
Gastrointest Liver Physiol 272: G1236 G1242, 1997.
678. Lo CW, Paris PW, Clemens TL, Nolan J, Holick MF. Vitamin D absorption in healthy
subjects and in patients with intestinal malabsorption syndromes. Am J Clin Nutr 42:
644 649, 1985.
679. Locklin RM, Khosla S, Turner RT, Riggs BL. Mediators of the biphasic responses of
bone to intermittent and continuously administered parathyroid hormone. J Cell
Biochem 89: 180 190, 2003.
680. Loffing J, Loffing-Cueni D, Valderrabano V, Klausli L, Hebert SC, Rossier BC, Hoenderop JG, Bindels RJ, Kaissling B. Distribution of transcellular calcium and sodium
transport pathways along mouse distal nephron. Am J Physiol Renal Physiol 281:
F1021F1027, 2001.
681. Lorenz S, Frenzel R, Paschke R, Breitwieser GE, Miedlich SU. Functional desensitization of the extracellular calcium-sensing receptor is regulated via distinct mechanisms: role of G protein-coupled receptor kinases, protein kinase C and beta-arrestins. Endocrinology 148: 2398 2404, 2007.
682. Lotscher M, Scarpetta Y, Levi M, Halaihel N, Wang H, Zajicek HK, Biber J, Murer H,
Kaissling B. Rapid downregulation of rat renal Na/Pi cotransporter in response to
parathyroid hormone involves microtubule rearrangement. J Clin Invest 104: 483
494, 1999.
683. Lu P, Boros S, Chang Q, Bindels RJ, Hoenderop JG. The -glucuronidase klotho
exclusively activates the epithelial Ca2 channels TRPV5 and TRPV6. Nephrol Dialysis Transplantation 23: 33973402, 2008.
684. Luiz de Freitas PH, Li M, Ninomiya T, Nakamura M, Ubaidus S, Oda K, Udagawa N,
Maeda T, Takagi R, Amizuka N. Intermittent PTH administration stimulates preosteoblastic proliferation without leading to enhanced bone formation in osteoclastless c-fos(/) mice. J Bone Miner Res 24: 1586 1597, 2009.
685. Lund B, Selnes A. Plasma 1,25-dihydroxyvitamin D levels in pregnancy and lactation.
Acta Endocrinol 92: 330 335, 1979.
686. Lund J, DeLuca HF. Biologically active metabolite of vitamin D3 from bone, liver, and
blood serum. J Lipid Res 7: 739 744, 1966.
687. Lytton J. Na/Ca2 exchangers: three mammalian gene families control Ca2 transport. Biochem J 406: 365382, 2007.
688. Lytton J, Li XF, Dong H, Kraev A. K-dependent Na/Ca2 exchangers in the brain.
Ann NY Acad Sci 976: 382393, 2002.
255
712. Marks HD, Fleet JC, Peleg S. Transgenic expression of the human Vitamin D receptor (hVDR) in the duodenum of VDR-null mice attenuates the age-dependent decline
in calcium absorption. J Steroid Biochem Mol Biol 103: 513516, 2007.
733. Mellanby E. An experimental investigation on rickets. Lancet 193: 407 412, 1919.
713. Martin DL, DeLuca HF. Influence of sodium on calcium transport by the rat small
intestine. Am J Physiol 216: 13511359, 1969.
714. Martin SR, Linse S, Johansson C, Bayley PM, Forsen S. Protein surface charges and
Ca2 binding to individual sites in calbindin D9k: stopped-flow studies. Biochemistry
29: 4188 4193, 1990.
735. Meredith SC, Bolt MJ, Rosenberg IH. The supramolecular structure of vitamin D3 in
water. J Colloid Interface Sci 99: 244 255, 1984.
715. Martinez V, Curi AP, Torkian B, Schaeffer JM, Wilkinson HA, Walsh JH, Tache Y.
High basal gastric acid secretion in somatostatin receptor subtype 2 knockout mice.
Gastroenterology 114: 11251132, 1998.
736. Meyer MB, Watanuki M, Kim S, Shevde NK, Pike JW. The human transient receptor
potential vanilloid type 6 distal promoter contains multiple vitamin D receptor binding sites that mediate activation by 1,25-dihydroxyvitamin D3 in intestinal cells. Mol
Endocrinol 20: 14471461, 2006.
716. Martz A, Forte LR, Langeluttig SG. Renal cAMP and 1,25(OH)2D3 synthesis in estrogen-treated chick embryos and hens. Am J Physiol Endocrinol Metab 249: E626
E633, 1985.
717. Massheimer V, Boland R, de Boland AR. Rapid 1,25(OH)2-vitamin D3 stimulation of
calcium uptake by rat intestinal cells involves a dihydropyridine-sensitive cAMPdependent pathway. Cell Signal 6: 299 304, 1994.
256
718. Massry SG, Coburn JW, Chapman LW, Kleeman CR. Role of serum Ca, parathyroid
hormone, NaCl infusion on renal Ca and Na clearances. Am J Physiol 214: 1403
1409, 1968.
737. Miampamba M, Germano PM, Arli S, Wong HH, Scott D, Tache Y, Pisegna JR.
Expression of pituitary adenylate cyclase-activating polypeptide and PACAP type 1
receptor in the rat gastric and colonic myenteric neurons. Regul Pept 105: 145154,
2002.
from ECL carcinoid tumor of Mastomys natalensis. Biochem Biophys Res Commun
187: 11511157, 1992.
753. Mosekilde L, Sogaard CH, Danielsen CC, Torring O. The anabolic effects of human
parathyroid hormone (hPTH) on rat vertebral body mass are also reflected in the
quality of bone, assessed by biomechanical testing: a comparison study between
hPTH-(134) and hPTH-(1 84). Endocrinology 129: 421 428, 1991.
773. Nandi J, Bosche MC, Levine RA. Effects of a phorbol ester and isoquinoline sulfonamides on rabbit parietal cell function. J Pharmacol Exp Ther 279: 97105, 1996.
774. Nandi J, Loo A, Kim SW, Levine RA. Expression and characterization of protein
kinase C in isolated rabbit parietal cells. Int J Mol Med 3: 521526, 1999.
754. Motoyama HI, Friedman PA. Calcium-sensing receptor regulation of PTH-dependent calcium absorption by mouse cortical ascending limbs. Am J Physiol Renal Physiol
283: F399 F406, 2002.
775. Napoli N, Pedone C, Pozzilli P, Lauretani F, Bandinelli S, Ferrucci L, Incalzi RA. Effect
of ghrelin on bone mass density: the InChianti study. Bone 49: 257263, 2011.
755. Muallem S, Fimmel CJ, Pandol SJ, Sachs G. Regulation of free cytosolic Ca2 in the
peptic and parietal cells of the rabbit gastric gland. J Biol Chem 261: 2660 2667,
1986.
776. Naro F, Perez M, Migliaccio S, Galson DL, Orcel P, Teti A, Goldring SR. Phospholipase D- and protein kinase C isoenzyme-dependent signal transduction pathways
activated by the calcitonin receptor. Endocrinology 139: 32413248, 1998.
756. Muallem S, Karlish SJ. Studies on the mechanism of regulation of the red-cell Ca2
pump by calmodulin and ATP. Biochim Biophys Acta 647: 73 86, 1981.
777. Natalucci G, Riedl S, Gleiss A, Zidek T, Frisch H. Spontaneous 24-h ghrelin secretion
pattern in fasting subjects: maintenance of a meal-related pattern. Eur J Endocrinol
152: 845 850, 2005.
757. Muhe L, Lulseged S, Mason KE, Simoes EA. Case-control study of the role of nutritional rickets in the risk of developing pneumonia in Ethiopian children. Lancet 349:
18011804, 1997.
758. Mulderry PK, Ghatei MA, Spokes RA, Jones PM, Pierson AM, Hamid QA, Kanse S,
Amara SG, Burrin JM, Legon S. Differential expression of alpha-CGRP and betaCGRP by primary sensory neurons and enteric autonomic neurons of the rat. Neuroscience 25: 195205, 1988.
760. Mungan Z, Hammer RA, Akarca US, Komaki G, Ertan A, Arimura A. Effect of PACAP
on gastric acid secretion in rats. Peptides 16: 10511056, 1995.
761. Munson K, Garcia R, Sachs G. Inhibitor and ion binding sites on the gastric H-KATPase. Biochemistry 44: 52675284, 2005.
762. Munson K, Law RJ, Sachs G. Analysis of the gastric H,K ATPase for ion pathways and
inhibitor binding sites. Biochemistry 46: 5398 5417, 2007.
763. Murayama A, Takeyama K, Kitanaka S, Kodera Y, Hosoya T, Kato S. The promoter
of the human 25-hydroxyvitamin D3 1 alpha-hydroxylase gene confers positive and
negative responsiveness to PTH, calcitonin, and 1 alpha,25(OH)2D3. Biochem Biophys Res Commun 249: 1116, 1998.
764. Murayama A, Takeyama K, Kitanaka S, Kodera Y, Kawaguchi Y, Hosoya T, Kato S.
Positive and negative regulations of the renal 25-hydroxyvitamin D3 1alpha-hydroxylase gene by parathyroid hormone, calcitonin, and 1alpha,25(OH)2D3 in intact
animals. Endocrinology 140: 2224 2231, 1999.
765. Murer H, Hernando N, Forster I, Biber J. Proximal tubular phosphate reabsorption:
molecular mechanisms. Physiol Rev 80: 13731409, 2000.
766. Murray CB, Morales MM, Flotte TR, McGrath-Morrow SA, Guggino WB, Zeitlin PL.
CIC-2: a developmentally dependent chloride channel expressed in the fetal lung and
downregulated after birth. Am J Respir Cell Mol Biol 12: 597 604, 1995.
787. Nguyen TM, Lieberherr M, Fritsch J, Guillozo H, Alvarez ML, Fitouri Z, Jehan F,
Garabedian M. The rapid effects of 1,25-dihydroxyvitamin D3 require the vitamin D
receptor and influence 24-hydroxylase activity: studies in human skin fibroblasts
bearing vitamin D receptor mutations. J Biol Chem 279: 75917597, 2004.
768. Nakajima K, Nohtomi K, Sato M, Takano K, Sato K. PTH(7 84) inhibits PTH(134)induced 1,25-(OH)2D3 production in murine renal tubules. Biochem Biophys Res
Commun 381: 283287, 2009.
788. Niall HD, Keutmann H, Sauer R, Hogan M, Dawson B, Aurbach G, Potts J Jr. The
amino acid sequence of bovine parathyroid hormone I. Hoppe-Seylers Z Physiol Chem
351: 1586 1588, 1970.
789. Nicar MJ, Pak CY. Calcium bioavailability from calcium carbonate and calcium citrate. J Clin Endocrinol Metab 61: 391393, 1985.
790. Nicholson GC, Moseley JM, Sexton PM, Mendelsohn FA, Martin TJ. Abundant calcitonin receptors in isolated rat osteoclasts. Biochemical and autoradiographic characterization. J Clin Invest 78: 355360, 1986.
791. Niemeyer BA, Bergs C, Wissenbach U, Flockerzi V, Trost C. Competitive regulation
of CaT-like-mediated Ca2 entry by protein kinase C and calmodulin. Proc Natl Acad
Sci USA 98: 3600 3605, 2001.
792. Nijenhuis T, Hoenderop JG, van der Kemp AW, Bindels RJ. Localization and regulation of the epithelial Ca2 channel TRPV6 in the kidney. J Am Soc Nephrol 14:
27312740, 2003.
257
759. Mun HC, Franks AH, Culverston EL, Krapcho K, Nemeth EF, Conigrave AD. The
Venus Fly Trap domain of the extracellular Ca2-sensing receptor is required for
L-amino acid sensing. J Biol Chem 279: 51739 51744, 2004.
802. Norman AW, Olivera CJ, Barreto Silva FR, Bishop JE. A specific binding protein/
receptor for 1alpha,25-dihydroxyvitamin D(3) is present in an intestinal caveolae
membrane fraction. Biochem Biophys Res Commun 298: 414 419, 2002.
814. Okunade GW, Miller ML, Pyne GJ, Sutliff RL, OConnor KT, Neumann JC, Andringa
A, Miller DA, Prasad V, Doetschman T, Paul RJ, Shull GE. Targeted ablation of plasma
membrane Ca2-ATPase (PMCA) 1 and 4 indicates a major housekeeping function
for PMCA1 and a critical role in hyperactivated sperm motility and male fertility for
PMCA4. J Biol Chem 279: 3374233750, 2004.
815. Olesen C, Picard M, Winther AML, Gyrup C, Morth JP, Oxvig C, Moller JV, Nissen
P. The structural basis of calcium transport by the calcium pump. Nature 450:
1036 1042, 2007.
816. Oscarson J, Hakanson R, Liedberg G, Lundqvist G, Sundler F, Thorell J. Variated
serum gastrin concentration: trophic effects on the gastrointestinal tract of the rat.
Acta Physiol Scand Suppl 475: 227, 1979.
817. Owen TA, Aronow MS, Barone LM, Bettencourt B, Stein GS, Lian JB. Pleiotropic
effects of vitamin D on osteoblast gene expression are related to the proliferative
and differentiated state of the bone cell phenotype: dependency upon basal levels of
gene expression, duration of exposure, and bone matrix competency in normal rat
osteoblast cultures. Endocrinology 128: 1496 1504, 1991.
818. Owyang C, Miller LJ, DiMagno EP, Brennan LA Jr, Go VL. Gastrointestinal hormone
profile in renal insufficiency. Mayo Clin Proc 54: 769 773, 1979.
819. Paillard F, Ardaillou R, Malendin H, Fillastre JP, Prier S. Renal effects of salmon
calcitonin in man. J Lab Clin Med 80: 200 216, 1972.
820. Pan Q, Ma J, Zhou Q, Li J, Tang Y, Liu Y, Yang Y, Xiao J, Peng L, Li P, Liang D, Zhang
H, Chen YH. KCNQ1 loss-of-function mutation impairs gastric acid secretion in
mice. Mol Biol Rep 37: 1329 1333, 2010.
821. Panda DK, Miao D, Bolivar I, Li J, Huo R, Hendy GN, Goltzman D. Inactivation of the
25-hydroxyvitamin D 1alpha-hydroxylase and vitamin D receptor demonstrates independent and interdependent effects of calcium and vitamin D on skeletal and
mineral homeostasis. J Biol Chem 279: 16754 16766, 2004.
803. Noto T, Nagasaki M, Endo T. Role of vagus nerves and gastrin in the gastric phase of
acid secretion in male anesthetized rats. Am J Physiol Gastrointest Liver Physiol 272:
G335G339, 1997.
822. Panda DK, Miao D, Tremblay ML, Sirois J, Farookhi R, Hendy GN, Goltzman D.
Targeted ablation of the 25-hydroxyvitamin D 1alpha-hydroxylase enzyme: evidence for skeletal, reproductive, and immune dysfunction. Proc Natl Acad Sci USA 98:
7498 7503, 2001.
804. Nuttall ME, Patton AJ, Olivera DL, Nadeau DP, Gowen M. Human trabecular bone
cells are able to express both osteoblastic and adipocytic phenotype: implications for
osteopenic disorders. J Bone Miner Res 13: 371382, 1998.
805. Nykjaer A, Dragun D, Walther D, Vorum H, Jacobsen C, Herz J, Melsen F, Christensen EI, Willnow TE. An endocytic pathway essential for renal uptake and activation of the steroid 25-(OH) vitamin D3. Cell 96: 507515, 1999.
806. Nykjaer A, Fyfe JC, Kozyraki R, Leheste JR, Jacobsen C, Nielsen MS, Verroust PJ,
Aminoff M, de la Chapelle A, Moestrup SK, Ray R, Gliemann J, Willnow TE, Christensen EI. Cubilin dysfunction causes abnormal metabolism of the steroid hormone
25(OH) vitamin D(3). Proc Natl Acad Sci USA 98: 1389513900, 2001.
825. Pansu D, Bellaton C, Roche C, Bronner F. Duodenal and ileal calcium absorption in
the rat and effects of vitamin D. Am J Physiol Gastrointest Liver Physiol 244: G695
G700, 1983.
807. OConnell MB, Madden DM, Murray AM, Heaney RP, Kerzner LJ. Effects of proton
pump inhibitors on calcium carbonate absorption in women: a randomized crossover trial. Am J Med 118: 778 781, 2005.
808. Offermanns S, Iida-Klein A, Segre GV, Simon MI. G alpha q family members couple
parathyroid hormone (PTH)/PTH-related peptide and calcitonin receptors to phospholipase C in COS-7 cells. Mol Endocrinol 10: 566 574, 1996.
809. Oginni LM, Worsfold M, Oyelami OA, Sharp CA, Powell DE, Davie MW. Etiology of
rickets in Nigerian children. J Pediatr 128: 692 694, 1996.
810. Oh DS, Lieu SN, Yamaguchi DJ, Tachiki K, Lambrecht N, Ohning GV, Sachs G,
Germano PM, Pisegna JR. PACAP regulation of secretion and proliferation of pure
populations of gastric ECL cells. J Mol Neurosci 26: 8597, 2005.
811. Oh KW, Lee WY, Rhee EJ, Baek KH, Yoon KH, Kang MI, Yun EJ, Park CY, Ihm SH,
Choi MG, Yoo HJ, Park SW. The relationship between serum resistin, leptin, adiponectin, ghrelin levels and bone mineral density in middle-aged men. Clin Endocrinol
63: 131138, 2005.
812. Ohyama Y, Ozono K, Uchida M, Yoshimura M, Shinki T, Suda T, Yamamoto O.
Functional assessment of two vitamin D-responsive elements in the rat 25-hydroxyvitamin D3 24-hydroxylase gene. J Biol Chem 271: 3038130385, 1996.
258
826. Parhon C, Ureche CS. Untersuchungen uber den Einfluss den die Calcium und
Sodiumsalze auf den Verlauf der experimentellen Tetanie ausuben. Neurol Centr 26:
1099, 1907.
827. Park J, Chiba T, Yamada T. Mechanisms for direct inhibition of canine gastric parietal
cells by somatostatin. J Biol Chem 262: 14190 14196, 1987.
828. Parkinson DB, Thakker RV. A donor splice site mutation in the parathyroid hormone
gene is associated with autosomal recessive hypoparathyroidism. Nat Genet 1: 149
152, 1992.
829. Parthemore JG, Deftos LJ. Calcitonin secretion in normal human subjects. J Clin
Endocrinol Metab 47: 184 188, 1978.
830. Patterson EK, Hodsman AB, Hendy GN, Canaff L, Bringhurst FR, Fraher LJ. Functional analysis of a type 1 parathyroid hormone receptor intracellular tail mutant
[KRK(484 6)AAA]: effects on second messenger generation and cellular targeting.
Bone 46: 1180 1187, 2010.
831. Patton MB. Further experiments on the utilization of calcium from salts by college
women. J Nutr 55: 519 526, 1955.
832. Patton MB, Sutton TS. The utilization of calcium from lactate, gluconate, sulfate and
carbonate salts by young college women. J Nutr 48: 443 452, 1952.
801. Norman AW, Okamura WH, Hammond MW, Bishop JE, Dormanen MC, Bouillon R, van Baelen H, Ridall AL, Daane E, Khoury R, Farach-Carson MC. Comparison of 6-s-cis- and 6-s-trans-locked analogs of 1alpha,25-dihydroxyvitamin
D3 indicates that the 6-s-cis conformation is preferred for rapid nongenomic
biological responses and that neither 6-s-cis- nor 6-s-trans-locked analogs are
preferred for genomic biological responses. Mol Endocrinol 11: 1518 1531,
1997.
813. Okamoto CT, Karam SM, Jeng YY, Forte JG, Goldenring JR. Identification of clathrin
and clathrin adaptors on tubulovesicles of gastric acid secretory (oxyntic) cells. Am J
Physiol Cell Physiol 274: C1017C1029, 1998.
854. Pi M, Zhang L, Lei SF, Huang MZ, Zhu W, Zhang J, Shen H, Deng HW, Quarles LD.
Impaired osteoblast function in GPRC6A null mice. J Bone Miner Res 25: 10921102,
2010.
834. Pearce SH, Bai M, Quinn SJ, Kifor O, Brown EM, Thakker RV. Functional characterization of calcium-sensing receptor mutations expressed in human embryonic kidney
cells. J Clin Invest 98: 1860 1866, 1996.
856. Pickard BW, Hodsman AB, Fraher LJ, Watson PH. Type 1 parathyroid hormone
receptor (PTH1R) nuclear trafficking: association of PTH1R with importin alpha1
and beta. Endocrinology 147: 3326 3332, 2006.
836. Peng JB, Brown EM, Hediger MA. Structural conservation of the genes encoding
CaT1, CaT2, and related cation channels. Genomics 76: 99 109, 2001.
837. Peng JB, Chen XZ, Berger UV, Vassilev PM, Brown EM, Hediger MA. A rat kidneyspecific calcium transporter in the distal nephron. J Biol Chem 275: 28186 28194,
2000.
838. Peng JB, Chen XZ, Berger UV, Vassilev PM, Tsukaguchi H, Brown EM, Hediger MA.
Molecular cloning and characterization of a channel-like transporter mediating intestinal calcium absorption. J Biol Chem 274: 22739 22746, 1999.
839. Peng JB, Zhuang L, Berger UV, Adam RM, Williams BJ, Brown EM, Hediger MA,
Freeman MR. CaT1 expression correlates with tumor grade in prostate cancer.
Biochem Biophys Res Commun 282: 729 734, 2001.
840. Perez JF, Ruiz MC, Michelangeli F. Simultaneous measurement and imaging of intracellular Ca2 and H transport in isolated rabbit gastric glands. J Physiol 537: 735
745, 2001.
259
841. Persson P, Gagnemo-Persson R, Chen D, Axelson J, Nylander AG, Johnell O, Hakanson R. Gastrectomy causes bone loss in the rat: is lack of gastric acid responsible?
Scand J Gastroenterol 28: 301306, 1993.
857. Pickard BW, Hodsman AB, Fraher LJ, Watson PH. Type 1 parathyroid hormone
receptor (PTH1R) nuclear trafficking: regulation of PTH1R nuclear-cytoplasmic
shuttling by importin-alpha/beta and chromosomal region maintenance 1/exportin 1.
Endocrinology 148: 22822289, 2007.
897. Reeve J, Meunier PJ, Parsons JA, Bernat M, Bijvoet OL, Courpron P, Edouard C,
Klenerman L, Neer RM, Renier JC, Slovik D, Vismans FJ, Potts JT Jr. Anabolic effect
of human parathyroid hormone fragment on trabecular bone in involutional osteoporosis: a multicentre trial. Br Med J 280: 1340 1344, 1980.
898. Reiss AB, Martin KO, Rojer DE, Iyer S, Grossi EA, Galloway AC, Javitt NB. Sterol
27-hydroxylase: expression in human arterial endothelium. J Lipid Res 38: 1254
1260, 1997.
877. Quamme GA. Effect of calcitonin on calcium and magnesium transport in rat
nephron. Am J Physiol Endocrinol Metab 238: E573E578, 1980.
899. Remy C, Kirchhoff P, Hafner P, Busque SM, Mueller MK, Geibel JP, Wagner CA.
Stimulatory pathways of the Calcium-sensing receptor on acid secretion in freshly
isolated human gastric glands. Cell Physiol Biochem 19: 33 42, 2007.
878. Quinn JM, Morfis M, Lam MH, Elliott J, Kartsogiannis V, Williams ED, Gillespie MT,
Martin TJ, Sexton PM. Calcitonin receptor antibodies in the identification of osteoclasts. Bone 25: 1 8, 1999.
879. Quinn SJ, Bai M, Brown EM. pH Sensing by the calcium-sensing receptor. J Biol Chem
279: 3724137249, 2004.
901. Renkema KY, Velic A, Dijkman HB, Verkaart S, van der Kemp AW, Nowik M,
Timmermans K, Doucet A, Wagner CA, Bindels RJ, Hoenderop JG. The calciumsensing receptor promotes urinary acidification to prevent nephrolithiasis. J Am Soc
Nephrol 20: 17051713, 2009.
880. Quinn SJ, Ye CP, Diaz R, Kifor O, Bai M, Vassilev P, Brown E. The Ca2-sensing
receptor: a target for polyamines. Am J Physiol Cell Physiol 273: C1315C1323, 1997.
881. Raczynski J. Recherches exprimentales sur le manque daction du soleil comme
cause du rachitisme. In: C R Assoc Internat Pediatrie. Paris: 1912, p. 308 309.
882. Rakopoulos M, Ikegame M, Findlay DM, Martin TJ, Moseley JM. Short treatment of
osteoclasts in bone marrow culture with calcitonin causes prolonged suppression of
calcitonin receptor mRNA. Bone 17: 447 453, 1995.
884. Rautureau M, Rambaud JC. Aqueous solubilisation of vitamin D3 in normal man. Gut
22: 393397, 1981.
885. Ravazzola M, Benoit R, Ling N, Orci L. Prosomatostatin-derived antrin is present in
gastric D cells and in portal blood. J Clin Invest 83: 362366, 1989.
886. Ray JM, Squires PE, Curtis SB, Meloche MR, Buchan AM. Expression of the calciumsensing receptor on human antral gastrin cells in culture. J Clin Invest 99: 2328 2333,
1997.
887. Ray K, Clapp P, Goldsmith PK, Spiegel AM. Identification of the sites of N-linked
glycosylation on the human calcium receptor and assessment of their role in cell
surface expression and signal transduction. J Biol Chem 273: 34558 34567, 1998.
888. Ray K, Hauschild BC, Steinbach PJ, Goldsmith PK, Hauache O, Spiegel AM. Identification of the cysteine residues in the amino-terminal extracellular domain of the
human Ca2 receptor critical for dimerization. Implications for function of monomeric Ca2 receptor. J Biol Chem 274: 2764227650, 1999.
889. Raychowdhury R, Fleming JV, McLaughlin JT, Bulitta CJ, Wang TC. Identification and
characterization of a third gastrin response element (GAS-RE3) in the human histidine decarboxylase gene promoter. Biochem Biophys Res Commun 297: 1089 1095,
2002.
890. Raychowdhury R, Zhang Z, Hocker M, Wang TC. Activation of human histidine
decarboxylase gene promoter activity by gastrin is mediated by two distinct nuclear
factors. J Biol Chem 274: 2096120969, 1999.
903. Resnick RH, Adelardi CF, Gray SJ. Stimulation of gastric secretion in man by a
serotonin antagonist. Gastroenterology 42: 2225, 1962.
904. Reubi JC, Waser B, Horisberger U, Halter F, Soroka CJ, Kumar RR, Goldenring JR,
Modlin IM. Identification of somatostatin and gastrin receptors on enterochromaffinlike cells from Mastomys gastric tumors. Endocrinology 131: 166 172, 1992.
905. Reubi JC, Waser B, Laderach U, Stettler C, Friess H, Halter F, Schmassmann A.
Localization of cholecystokinin A and cholecystokinin B-gastrin receptors in the
human stomach. Gastroenterology 112: 11971205, 1997.
906. Riccardi D, Brown EM. Physiology and pathophysiology of the calcium-sensing receptor in the kidney. Am J Physiol Renal Physiol 298: F485F499, 2010.
907. Riccardi D, Hall AE, Chattopadhyay N, Xu JZ, Brown EM, Hebert SC. Localization of
the extracellular Ca2/polyvalent cation-sensing protein in rat kidney. Am J Physiol
Renal Physiol 274: F611F622, 1998.
908. Riccardi D, Lee WS, Lee K, Segre GV, Brown EM, Hebert SC. Localization of the
extracellular Ca2-sensing receptor and PTH/PTHrP receptor in rat kidney. Am J
Physiol Renal Fluid Electrolyte Physiol 271: F951F956, 1996.
909. Riccardi D, Traebert M, Ward DT, Kaissling B, Biber J, Hebert SC, Murer H. Dietary
phosphate and parathyroid hormone alter the expression of the calcium-sensing
receptor (CaR) and the Na-dependent Pi transporter (NaPi-2) in the rat proximal
tubule. Pflgers Arch 441: 379 387, 2000.
910. Richardson CT, Walsh JH, Cooper KA, Feldman M, Fordtran JS. Studies on the role
of cephalic-vagal stimulation in the acid secretory response to eating in normal
human subjects. J Clin Invest 60: 435 441, 1977.
891. Recker RR. Calcium absorption and achlorhydria. N Engl J Med 313: 70 73, 1985.
892. Reddy GS, Norman AW, Willis DM, Goltzman D, Guyda H, Solomon S, Philips DR,
Bishop JE, Mayer E. Regulation of vitamin D metabolism in normal human pregnancy.
J Clin Endocrinol Metab 56: 363370, 1983.
893. Reddy GS, Tserng KY. Calcitroic acid, end product of renal metabolism of 1,25dihydroxyvitamin D3 through C-24 oxidation pathway. Biochemistry 28: 17631769,
1989.
913. Robinson CJ, Spanos E, James MF, Pike JW, Haussler MR, Makeen AM, Hillyard CJ,
MacIntyre I. Role of prolactin in vitamin D metabolism and calcium absorption during
lactation in the rat. J Endocrinol 94: 443 453, 1982.
894. Reed JS, Meredith SC, Nemchausky BA, Rosenberg IH, Boyer JL. Bone disease in
primary biliary cirrhosis: reversal of osteomalacia with oral 25-hydroxyvitamin D.
Gastroenterology 78: 512517, 1980.
914. Rochel N, Wurtz JM, Mitschler A, Klaholz B, Moras D. The crystal structure of the
nuclear receptor for vitamin D bound to its natural ligand. Mol Cell 5: 173179, 2000.
260
902. Repa JJ, Lund EG, Horton JD, Leitersdorf E, Russell DW, Dietschy JM, Turley SD.
Disruption of the sterol 27-hydroxylase gene in mice results in hepatomegaly and
hypertriglyceridemia. Reversal by cholic acid feeding. J Biol Chem 275: 3968539692,
2000.
936. Sachs G, Shin JM, Briving C, Wallmark B, Hersey S. The pharmacology of the gastric
acid pump: the H,K ATPase. Annu Rev Pharmacol Toxicol 35: 277305, 1995.
917. Roepke TK, Anantharam A, Kirchhoff P, Busque SM, Young JB, Geibel JP, Lerner DJ,
Abbott GW. The KCNE2 potassium channel ancillary subunit is essential for gastric
acid secretion. J Biol Chem 281: 23740 23747, 2006.
937. Safadi FF, Thornton P, Magiera H, Hollis BW, Gentile M, Haddad JG, Liebhaber SA,
Cooke NE. Osteopathy and resistance to vitamin D toxicity in mice null for vitamin
D binding protein. J Clin Invest 103: 239 251, 1999.
918. Rosen H, Reshef A, Maeda N, Lippoldt A, Shpizen S, Triger L, Eggertsen G, Bjorkhem I, Leitersdorf E. Markedly reduced bile acid synthesis but maintained levels of
cholesterol and vitamin D metabolites in mice with disrupted sterol 27-hydroxylase
gene. J Biol Chem 273: 1480514812, 1998.
919. Rosenblatt M, Segre GV, Tyler GA, Shepard GL, Nussbaum SR, Potts JT Jr. Identification of a receptor-binding region in parathyroid hormone. Endocrinology 107:
545550, 1980.
920. Ross TK, Darwish HM, Moss VE, DeLuca HF. Vitamin D-influenced gene expression
via a ligand-independent, receptor-DNA complex intermediate. Proc Natl Acad Sci
USA 90: 92579260, 1993.
921. Rost CR, Bikle DD, Kaplan RA. In vitro stimulation of 25-hydroxycholecalciferol 1
alpha-hydroxylation by parathyroid hormone in chick kidney slices: evidence for a
role for adenosine 3=,5=-monophosphate. Endocrinology 108: 10021006, 1981.
922. Roth J, Thorens B, Hunziker W, Norman AW, Orci L. Vitamin D-dependent calcium
binding protein: immunocytochemical localization in chick kidney. Science 214: 197
200, 1981.
923. Roux C, Briot K, Gossec L, Kolta S, Blenk T, Felsenberg D, Reid DM, Eastell R, Gler
CC. Increase in vertebral fracture risk in postmenopausal women using omeprazole.
Calcified Tissue Int 84: 1319, 2009.
925. Rowe DW, Kream BE. Regulation of collagen synthesis in fetal rat calvaria by 1,25dihydroxyvitamin D3. J Biol Chem 257: 8009 8015, 1982.
926. Rowling MJ, Kemmis CM, Taffany DA, Welsh J. Megalin-mediated endocytosis of
vitamin D binding protein correlates with 25-hydroxycholecalciferol actions in human mammary cells. J Nutr 136: 2754 2759, 2006.
927. Rumenapf G, Schwille PO, Erben RG, Schreiber M, Berge B, Fries W, Schmiedl A,
Koroma S, Hohenberger W. Gastric fundectomy in the rat: effects on mineral and
bone metabolism, with emphasis on the gastrin-calcitonin-parathyroid hormonevitamin D axis. Calcif Tissue Int 63: 433 441, 1998.
928. Rumenapf G, Schwille PO, Wagner W, Tiecks FP, Fries W, Galewski D. Highly
selective vagotomy in the rat: effects on bone and mineral metabolism. Scand J
Gastroenterol 29: 232237, 1994.
929. Rune SJ. Acid-base parameters of duodenal contents in man. Gastroenterology 62:
533539, 1972.
930. Russell J, Bar A, Sherwood LM, Hurwitz S. Interaction between calcium and 1,25dihydroxyvitamin D3 in the regulation of preproparathyroid hormone and vitamin D
receptor messenger ribonucleic acid in avian parathyroids. Endocrinology 132: 2639
2644, 1993.
931. Russell J, Lettieri D, Sherwood LM. Suppression by 1,25(OH)2D3 of transcription of
the pre-proparathyroid hormone gene. Endocrinology 119: 2864 2866, 1986.
932. Rutten MJ, Bacon KD, Marlink KL, Stoney M, Meichsner CL, Lee FP, Hobson SA,
Rodland KD, Sheppard BC, Trunkey DD, Deveney KE, Deveney CW. Identification
of a functional Ca2-sensing receptor in normal human gastric mucous epithelial
cells. Am J Physiol Gastrointest Liver Physiol 277: G662G670, 1999.
933. Saarem K, Pedersen JI. Sex differences in the hydroxylation of cholecalciferol and of
5 beta-cholestane-3 alpha,7 alpha,12 alpha-triol in rat liver. Biochem J 247: 7378,
1987.
941. Sandor A, Kidd M, Lawton GP, Miu K, Tang LH, Modlin IM. Neurohormonal modulation of rat enterochromaffin-like cell histamine secretion. Gastroenterology 110:
1084 1092, 1996.
942. Sands JM, Flores FX, Kato A, Baum MA, Brown EM, Ward DT, Hebert SC, Harris
HW. Vasopressin-elicited water and urea permeabilities are altered in IMCD in
hypercalcemic rats. Am J Physiol Renal Physiol 274: F978 F985, 1998.
943. Sands JM, Naruse M, Baum M, Jo I, Hebert SC, Brown EM, Harris HW. Apical
extracellular calcium/polyvalent cation-sensing receptor regulates vasopressin-elicited water permeability in rat kidney inner medullary collecting duct. J Clin Invest 99:
1399 1405, 1997.
944. Sandvik AK, Cui G, Bakke I, Munkvold B, Waldum HL. PACAP stimulates gastric acid
secretion in the rat by inducing histamine release. Am J Physiol Gastrointest Liver
Physiol 281: G997G1003, 2001.
945. Sandvik AK, Dimaline R, Forster ER, Evans D, Dockray GJ. Differential control of
somatostatin messenger RNA in rat gastric corpus and antrum. Role of acid, food,
and capsaicin-sensitive afferent neurons. J Clin Invest 91: 244 250, 1993.
946. Sandvik AK, Kleveland PM, Waldum HL. Muscarinic M2 stimulation releases histamine in the totally isolated, vascularly perfused rat stomach. Scand J Gastroenterol 23:
1049 1056, 1988.
947. Saperas E, Cominelli F, Tache Y. Potent inhibition of gastric acid secretion by intravenous interleukin-1 beta and -1 alpha in rats. Peptides 13: 221226, 1992.
948. Saperas E, Yang H, Tache Y. Interleukin-1 beta acts at hypothalamic sites to inhibit
gastric acid secretion in rats. Am J Physiol Gastrointest Liver Physiol 263: G414 G418,
1992.
949. Saperas ES, Yang H, Rivier C, Tache Y. Central action of recombinant interleukin-1
to inhibit acid secretion in rats. Gastroenterology 99: 1599 1606, 1990.
950. Sawada N, Sakaki T, Ohta M, Inouye K. Metabolism of vitamin D3 by human
CYP27A1. Biochem Biophys Res Commun 273: 977984, 2000.
951. Schachter D. Toward a molecular description of active transport. In: Biological Membranes, edited by Dowben RM. Boston: Little, Brown, 1969, p. 157176.
952. Schachter D, Dowdle EB, Schenker H. Active transport of calcium by the small
intestine of the rat. Am J Physiol 198: 263268, 1960.
953. Schachter D, Finkelstein JD, Kowarski S. Metabolism of vitamin D. I. Preparation of
radioactive vitamin D and its intestinal absorption in the rat. J Clin Invest 43: 787796,
1964.
954. Schachter D, Rosen SM. Active transport of Ca45 by the small intestine and its
dependence on vitamin D. Am J Physiol 196: 357362, 1959.
955. Schaffalitzky de Muckadell OB, Fahrenkrug J. Secretion pattern of secretin in man:
regulation by gastric acid. Gut 19: 812 818, 1978.
956. Schatzmann HJ. ATP-dependent Ca2-extrusion from human red cells. Experientia
22: 364 365, 1966.
934. Sabbieti MG, Agas D, Xiao L, Marchetti L, Coffin JD, Doetschman T, Hurley MM.
Endogenous FGF-2 is critically important in PTH anabolic effects on bone. J Cell
Physiol 219: 143151, 2009.
957. Schayer RW. Formation and binding of histamine by rat tissues in vitro. Am J Physiol
187: 63 65, 1956.
935. Saccomani G, Psarras CG, Smith PR, Kirk KL, Shoemaker RL. Histamine-induced
chloride channels in apical membrane of isolated rabbit parietal cells. Am J Physiol Cell
Physiol 260: C1000 C1011, 1991.
261
924. Rovner AJ, Stallings VA, Schall JI, Leonard MB, Zemel BS. Vitamin D insufficiency in
children, adolescents, and young adults with cystic fibrosis despite routine oral supplementation. Am J Clin Nutr 86: 1694 1699, 2007.
940. Sandle GI, Fraser G, Long S, Warhurst G. A cAMP-activated chloride channel in the
plasma membrane of cultured human gastric cells (HGT-1). Pflgers Arch 417: 259
263, 1990.
967. Schmitz F, Goke MN, Otte JM, Schrader H, Reimann B, Kruse ML, Siegel EG, Peters
J, Herzig KH, Folsch UR, Schmidt WE. Cellular expression of CCK-A and CCK-B/
gastrin receptors in human gastric mucosa. Regul Pept 102: 101110, 2001.
968. Schmorl G. (Editor). Verhandlungen der Deutschen Pathologischen Gesellschaft. Jena:
Gustav Fischer, 1909.
969. Schnoke M, Midura SB, Midura RJ. Parathyroid hormone suppresses osteoblast
apoptosis by augmenting DNA repair. Bone 45: 590 602, 2009.
970. Schoeber JP, Topala CN, Wang X, Diepens RJ, Lambers TT, Hoenderop JG, Bindels
RJ. RGS2 inhibits the epithelial Ca2 channel TRPV6. J Biol Chem 281: 29669 29674,
2006.
971. Schoeber JPH, Topala CN, Lee KP, Lambers TT, Ricard G, Van Der Kemp AWCM,
Huynen MA, Hoenderop JGJ, Bindels RJM. Identification of Nipsnap1 as a novel
auxiliary protein inhibiting TRPV6 activity. Pflgers Arch 457: 91101, 2008.
972. Schoen MS, Lindenbaum J, Roginsky MS, Holt PR. Significance of serum level of
25-hydroxycholecalciferol in gastrointestinal disease. Am J Dig Dis 23: 137142,
1978.
973. Schofield GC, Ito S, Bolender RP. Changes in membrane surface areas in mouse
parietal cells in relation to high levels of acid secretion. J Anat 128: 669 692, 1979.
974. Scholz D, Schwille PO, Schley HW, Hanisch E, Bieger D, Zeuner E, Engelhardt W.
Mineral metabolism and vitamin D status before and up to five years following highly
selective vagotomy in duodenal ulcer patients. Hepatogastroenterology 30: 102106,
1983.
975. Schubert ML, Edwards NF, Makhlouf GM. Regulation of gastric somatostatin secretion in the mouse by luminal acidity: a local feedback mechanism. Gastroenterology
94: 317322, 1988.
976. Schubert ML, Jong MJ, Makhlouf GM. Bombesin/GRP-stimulated somatostatin secretion is mediated by gastrin in the antrum and intrinsic neurons in the fundus. Am
J Physiol Gastrointest Liver Physiol 261: G885G889, 1991.
977. Schubert ML, Makhlouf GM. Gastrin secretion induced by distention is mediated by
gastric cholinergic and vasoactive intestinal peptide neurons in rats. Gastroenterology
104: 834 839, 1993.
978. Schubert ML, Saffouri B, Walsh JH, Makhlouf GM. Inhibition of neurally mediated
gastrin secretion by bombesin antiserum. Am J Physiol Gastrointest Liver Physiol 248:
G456 G462, 1985.
262
966. Schmidt WE, Schenk S, Nustede R, Holst JJ, Folsch UR, Creutzfeldt W. Cholecystokinin is a negative regulator of gastric acid secretion and postprandial release of
gastrin in humans. Gastroenterology 107: 1610 1620, 1994.
1007. Shin JM, Cho YM, Sachs G. Chemistry of covalent inhibition of the gastric (H ,
K)-ATPase by proton pump inhibitors. J Am Chem Soc 126: 7800 7811, 2004.
1022. Sneddon WB, Syme CA, Bisello A, Magyar CE, Rochdi MD, Parent JL, Weinman EJ,
Abou-Samra AB, Friedman PA. Activation-independent parathyroid hormone receptor internalization is regulated by NHERF1 (EBP50). J Biol Chem 278: 43787
43796, 2003.
1023. Soejima M, Tachida H, Koda Y. Sequence analysis of human TRPV6 suggests positive
selection outside Africa. Biochem Genet 47: 147153, 2009.
1024. Soll AH. The interaction of histamine with gastrin and carbamylcholine on oxygen
uptake by isolated mammalian parietal cells. J Clin Invest 61: 381389, 1978.
1025. Soll AH. Potentiating interactions of gastric stimulants on [14C]aminopyrine accumulation by isolated canine parietal cells. Gastroenterology 83: 216 223, 1982.
1026. Soll AH, Wollin A. Histamine and cyclic AMP in isolated canine parietal cells. Am J
Physiol Endocrinol Metab Gastrointest Physiol 237: E444 E450, 1979.
1027. Sone T, Kerner S, Pike JW. Vitamin D receptor interaction with specific DNA.
Association as a 1,25-dihydroxyvitamin D3-modulated heterodimer. J Biol Chem 266:
23296 23305, 1991.
1028. Song P, Groos S, Riederer B, Feng Z, Krabbenhoft A, Manns MP, Smolka A, Hagen SJ,
Neusch C, Seidler U. Kir4.1 channel expression is essential for parietal cell control of
acid secretion. J Biol Chem 286: 14120 14128, 2011.
1029. Song P, Groos S, Riederer B, Feng Z, Krabbenhoft A, Smolka A, Seidler U. KCNQ1
is the luminal K recycling channel during stimulation of gastric acid secretion. J
Physiol 587: 39553965, 2009.
1009. Shinki T, Ueno Y, DeLuca HF, Suda T. Calcitonin is a major regulator for the
expression of renal 25-hydroxyvitamin D3-1alpha-hydroxylase gene in normocalcemic rats. Proc Natl Acad Sci USA 96: 8253 8258, 1999.
1030. Song Y, Peng X, Porta A, Takanaga H, Peng JB, Hediger MA, Fleet JC, Christakos S.
Calcium transporter 1 and epithelial calcium channel messenger ribonucleic acid are
differentially regulated by 1,25 dihydroxyvitamin D3 in the intestine and kidney of
mice. Endocrinology 144: 38853894, 2003.
1010. Shoback DM, Membreno LA, McGhee JG. High calcium and other divalent cations
increase inositol trisphosphate in bovine parathyroid cells. Endocrinology 123: 382
389, 1988.
1011. Shulkes A, Read M. Regulation of somatostatin secretion by gastrin- and acid-dependent mechanisms. Endocrinology 129: 2329 2334, 1991.
1032. Sowa H, Kaji H, Iu MF, Tsukamoto T, Sugimoto T, Chihara K. Parathyroid hormoneSmaD3 axis exerts anti-apoptotic action and augments anabolic action of transforming growth factor beta in osteoblasts. J Biol Chem 278: 52240 52252, 2003.
1012. Shyjan AW, Canfield VA, Levenson R. Evolution of the Na,K- and H-K-ATPase
beta subunit gene family: structure of the murine Na-K-ATPase beta 2 subunit
gene. Genomics 11: 435 442, 1991.
1033. St-Arnaud R. The direct role of vitamin D on bone homeostasis. Arch Biochem Biophys
473: 225230, 2008.
1013. Sidani SM, Kirchhoff P, Socrates T, Stelter L, Ferreira E, Caputo C, Roberts KE, Bell
RL, Egan ME, Geibel JP. DeltaF508 mutation results in impaired gastric acid secretion. J Biol Chem 282: 6068 6074, 2007.
1034. St-Arnaud R, Messerlian S, Moir JM, Omdahl JL, Glorieux FH. The 25-hydroxyvitamin D 1-alpha-hydroxylase gene maps to the pseudovitamin D-deficiency rickets
(PDDR) disease locus. J Bone Miner Res 12: 15521559, 1997.
1014. Silve C, Petrel C, Leroy C, Bruel H, Mallet E, Rognan D, Ruat M. Delineating a Ca2
binding pocket within the venus flytrap module of the human calcium-sensing receptor. J Biol Chem 280: 3791737923, 2005.
1035. Stamp TC, Round JM. Seasonal changes in human plasma levels of 25-hydroxyvitamin
D. Nature 247: 563565, 1974.
1015. Silver J, Fainaru M. Transport of vitamin D sterols in human plasma: effect of excess
vitamin D, 25 hydroxyvitamin D and 1,25 dihydroxyvitamin D. Eur J Clin Invest 9:
433 438, 1979.
1016. Singer FR, Foster GV, Jpolin GF, Nadarajah A, Parkinson DK, Thalassinos N, Woodhouse NJ, Clark MB, Fraser TR, MacIntyre I. Acute effects of administered calcitonin
in man. Calcif Tissue Res Suppl: 20, 1968.
1017. Singh P, Velasco M, Given R, Varro A, Wang TC. Progastrin expression predisposes
mice to colon carcinomas and adenomas in response to a chemical carcinogen.
Gastroenterology 119: 162171, 2000.
1018. Sitrin MD, Bengoa JM. Intestinal absorption of cholecalciferol and 25-hydroxycholecalciferol in chronic cholestatic liver disease. Am J Clin Nutr 46: 10111015, 1987.
1019. Sitrin MD, Pollack KL, Bolt MJ, Rosenberg IH. Comparison of vitamin D and 25hydroxyvitamin D absorption in the rat. Am J Physiol Gastrointest Liver Physiol 242:
G326 G332, 1982.
1020. Sizemore GW, Go VL, Kaplan EL, Sanzenbacher LJ, Holtermuller KH, Arnaud CD.
Relations of calcitonin and gastrin in the Zollinger-Ellison syndrome and medullary
carcinoma of the thyroid. N Engl J Med 288: 641 644, 1973.
1036. Stedman CA, Barclay ML. Review article: comparison of the pharmacokinetics, acid
suppression and efficacy of proton pump inhibitors. Aliment Pharmacol Ther 14:
963978, 2000.
1037. Steenbock H, Black A. Fat-soluble vitamins. XVII. The induction of growth-promoting and calcifying properties in a ration by exposure to ultra-violet light. J Biol Chem
61: 405 422, 1924.
1038. Steggerda FR, Mitchell HH. The effect of the citrate ion on the calcium metabolism
of adult human subjects. J Nutr 31: 423 438, 1946.
1039. Stepan V, Pausawasdi N, Ramamoorthy S, Todisco A. The Akt and MAPK signaltransduction pathways regulate growth factor actions in isolated gastric parietal cells.
Gastroenterology 127: 1150 1161, 2004.
1040. Stepan V, Sugano K, Yamada T, Park J, Dickinson CJ. Gastrin biosynthesis in canine G
cells. Am J Physiol Gastrointest Liver Physiol 282: G766 G775, 2002.
1041. Sternfeld L, Anderie I, Schmid A, Al-Shaldi H, Krause E, Magg T, Schreiner D, Hofer
HW, Schulz I. Identification of tyrosines in the putative regulatory site of the Ca2
channel TRPV6. Cell Calcium 42: 91102, 2007.
1042. Sternfeld L, Krause E, Schmid A, Anderie I, Latas A, Al-Shaldi H, Kohl A, Evers K,
Hofer HW, Schulz I. Tyrosine phosphatase PTP1B interacts with TRPV6 in vivo and
263
264
1049. Suda J, Zhu L, Okamoto CT, Karvar S. Rab27b localizes to the tubulovesicle membranes of gastric parietal cells and regulates acid secretion. Gastroenterology 140:
868 878, 2011.
1061. Takahashi S, Goldring S, Katz M, Hilsenbeck S, Williams R, Roodman GD. Downregulation of calcitonin receptor mRNA expression by calcitonin during human osteoclast-like cell differentiation. J Clin Invest 95: 167171, 1995.
1083. Thompson PD, Jurutka PW, Haussler CA, Whitfield GK, Haussler MR. Heterodimeric DNA binding by the vitamin D receptor and retinoid X receptors is enhanced
by 1,25-dihydroxyvitamin D3 and inhibited by 9-cis-retinoic acid. Evidence for allosteric receptor interactions. J Biol Chem 273: 8483 8491, 1998.
1103. Usui E, Noshiro M, Okuda K. Molecular cloning of cDNA for vitamin D3 25-hydroxylase from rat liver mitochondria. FEBS Lett 262: 135138, 1990.
1084. Thunberg R. Localization of cells containing and forming histamine in the gastric
mucosa of the rat. Exp Cell Res 47: 108 115, 1967.
1085. Tian XQ, Chen TC, Matsuoka LY, Wortsman J, Holick MF. Kinetic and thermodynamic studies of the conversion of previtamin D3 to vitamin D3 in human skin. J Biol
Chem 268: 14888 14892, 1993.
1086. Tian XQ, Holick MF. A liposomal model that mimics the cutaneous production of
vitamin D3. Studies of the mechanism of the membrane-enhanced thermal isomerization of previtamin D3 to vitamin D3. J Biol Chem 274: 4174 4179, 1999.
1087. Tinel N, Diochot S, Borsotto M, Lazdunski M, Barhanin J. KCNE2 confers background current characteristics to the cardiac KCNQ1 potassium channel. EMBO J
19: 6326 6330, 2000.
1088. Tishkoff DX, Nibbelink KA, Holmberg KH, Dandu L, Simpson RU. Functional vitamin D receptor (VDR) in the t-tubules of cardiac myocytes: VDR knockout cardiomyocyte contractility. Endocrinology 149: 558 564, 2008.
1089. Tondapu P, Provost D, Adams-Huet B, Sims T, Chang C, Sakhaee K. Comparison of
the absorption of calcium carbonate and calcium citrate after Roux-en-Y gastric
bypass. Obes Surg 19: 1256 1261, 2009.
1091. Tovey FI, Karamanolis DG, Godfrey J, Clark CG. Post-gastrectomy nutrition: methods of outpatient screening for early osteomalacia. Hum Nutr Clin Nutr 39: 439 446,
1985.
1092. Toyoshima C, Nomura H. Structural changes in the calcium pump accompanying the
dissociation of calcium. Nature 418: 605 611, 2002.
1093. Toyoshima C, Nomura H, Sugita Y. Crystal structures of Ca2-ATPase in various
physiological states. Ann NY Acad Sci 986: 1 8, 2003.
1094. Tregear GW, Van Rietschoten J, Greene E, Keutmann HT, Niall HD, Reit B, Parsons
JA, Potts JT Jr. Bovine parathyroid hormone: minimum chain length of synthetic
peptide required for biological activity. Endocrinology 93: 1349 1353, 1973.
1095. Tsunoda Y, Funasaka M, Modlin IM, Hidaka H, Fox LM, Goldenring JR. An inhibitor
of Ca2/calmodulin-dependent protein kinase II, KN-62, inhibits cholinergic-stimulated parietal cell secretion. Am J Physiol Gastrointest Liver Physiol 262: G118 G122,
1992.
1105. Vagin O, Denevich S, Sachs G. Plasma membrane delivery of the gastric H-KATPase: the role of beta-subunit glycosylation. Am J Physiol Cell Physiol 285: C968
C976, 2003.
1106. Vagin O, Munson K, Lambrecht N, Karlish SJ, Sachs G. Mutational analysis of the
K-competitive inhibitor site of gastric H-K-ATPase. Biochemistry 40: 7480
7490, 2001.
1107. Vagne M, Andre C. The effect of secretin on gastric emptying in man. Gastroenterology 60: 421 424, 1971.
1108. Van Abel M, Hoenderop JG, van der Kemp AW, Friedlaender MM, van Leeuwen JP,
Bindels RJ. Coordinated control of renal Ca2 transport proteins by parathyroid
hormone. Kidney Int 68: 1708 1721, 2005.
1109. Van Abel M, Hoenderop JG, van der Kemp AW, van Leeuwen JP, Bindels RJ. Regulation of the epithelial Ca2 channels in small intestine as studied by quantitative
mRNA detection. Am J Physiol Gastrointest Liver Physiol 285: G78 G85, 2003.
1110. Van Cromphaut SJ, Dewerchin M, Hoenderop JG, Stockmans I, Van Herck E, Kato S,
Bindels RJ, Collen D, Carmeliet P, Bouillon R, Carmeliet G. Duodenal calcium absorption in vitamin D receptor-knockout mice: functional and molecular aspects.
Proc Natl Acad Sci USA 98: 13324 13329, 2001.
1111. Van de Graaf SF, Chang Q, Mensenkamp AR, Hoenderop JG, Bindels RJ. Direct
interaction with Rab11a targets the epithelial Ca2 channels TRPV5 and TRPV6 to
the plasma membrane. Mol Cell Biol 26: 303312, 2006.
1112. Van de Graaf SF, Hoenderop JG, Gkika D, Lamers D, Prenen J, Rescher U, Gerke V,
Staub O, Nilius B, Bindels RJ. Functional expression of the epithelial Ca2 channels
(TRPV5 and TRPV6) requires association of the S100A10-annexin 2 complex. EMBO
J 22: 1478 1487, 2003.
1113. Van de Graaf SF, Hoenderop JG, van der Kemp AW, Gisler SM, Bindels RJ. Interaction of the epithelial Ca2 channels TRPV5 and TRPV6 with the intestine- and
kidney-enriched PDZ protein NHERF4. Pflgers Arch 452: 407 417, 2006.
1114. Van Leeuwen JP, van Driel M, van den Bemd GJ, Pols HA. Vitamin D control of
osteoblast function and bone extracellular matrix mineralization. Crit Rev Eukaryot
Gene Expr 11: 199 226, 2001.
1115. Varrault A, Pena MS, Goldsmith PK, Mithal A, Brown EM, Spiegel AM. Expression of
G protein alpha-subunits in bovine parathyroid. Endocrinology 136: 4390 4396,
1995.
1116. Varro A, Green T, Holmes S, Dockray GJ. Calcitonin gene-related peptide in visceral
afferent nerve fibres: quantification by radioimmunoassay and determination of axonal transport rates. Neuroscience 26: 927932, 1988.
1097. Tucker G 3rd, Gagnon RE, Haussler MR. Vitamin D3-25-hydroxylase: tissue occurrence and apparent lack of regulation. Arch Biochem Biophys 155: 4757, 1973.
1118. Velluz L, Amirad G. Chimie organique-le precalciferol. Compt Rend Assoc Anat 228:
692 694, 1949.
1099. Tzaneva MA. Ultrastructural immunohistochemical localization of gastrin, somatostatin and serotonin in endocrine cells of human antral gastric mucosa. Acta Histochem 105: 191201, 2003.
1100. Uchida M, Teranishi H, Aoshima K, Katoh T, Kasuya M, Inadera H. Elevated urinary
levels of vitamin D-binding protein in the inhabitants of a cadmium polluted area,
Jinzu River basin, Japan. Tohoku J Exp Med 211: 269 274, 2007.
1101. Uehara A, Okumura T, Sekiya C, Okamura K, Takasugi Y, Namiki M. Interleukin-1
inhibits the secretion of gastric acid in rats: possible involvement of prostaglandin.
Biochem Biophys Res Commun 162: 1578 1584, 1989.
1102. Usatii M, Rousseau L, Demers C, Petit JL, Brossard JH, Gascon-Barre M, Lavigne JR,
Zahradnik RJ, Nemeth EF, DAmour P. Parathyroid hormone fragments inhibit ac-
265
1090. Topala CN, Schoeber JP, Searchfield LE, Riccardi D, Hoenderop JG, Bindels RJ.
Activation of the Ca2-sensing receptor stimulates the activity of the epithelial Ca2
channel TRPV5. Cell Calcium 45: 331339, 2009.
1143. Wang LD, Hoeltzel M, Gantz I, Hunter R, Del Valle J. Characterization of the histamine H2 receptor structural components involved in dual signaling. J Pharmacol Exp
Ther 285: 573578, 1998.
1124. Villa-Bellosta R, Ravera S, Sorribas V, Stange G, Levi M, Murer H, Biber J, Forster IC.
The Na-Pi cotransporter PiT-2 (SLC20A2) is expressed in the apical membrane of
rat renal proximal tubules and regulated by dietary Pi. Am J Physiol Renal Physiol 296:
F691F699, 2009.
1144. Wang Q, Curran ME, Splawski I, Burn TC, Millholland JM, VanRaay TJ, Shen J,
Timothy KW, Vincent GM, de Jager T, Schwartz PJ, Toubin JA, Moss AJ, Atkinson
DL, Landes GM, Connors TD, Keating MT. Positional cloning of a novel potassium
channel gene: KVLQT1 mutations cause cardiac arrhythmias. Nat Genet 12: 1723,
1996.
1125. Vinik AI, Gaginella TS, ODorisio TM, Shapiro B, Wagner L. The distribution and
characterization of somatostatin-like immunoreactivity in epithelial cells, submucosa, muscle of the rat stomach and intestine. Endocrinology 109: 19211926, 1981.
1126. Voets T, Janssens A, Prenen J, Droogmans G, Nilius B. Mg2-dependent gating and
strong inward rectification of the cation channel TRPV6. J Gen Physiol 121: 245260,
2003.
1127. Vogelsang H, Schofl R, Tillinger W, Ferenci P, Gangl A. 25-Hydroxyvitamin D absorption in patients with Crohns disease and with pancreatic insufficiency. Wien Klin
Wochenschr 109: 678 682, 1997.
1128. Wada M, Furuya Y, Sakiyama J, Kobayashi N, Miyata S, Ishii H, Nagano N. The
calcimimetic compound NPS R-568 suppresses parathyroid cell proliferation in rats
with renal insufficiency. Control of parathyroid cell growth via a calcium receptor. J
Clin Invest 100: 29772983, 1997.
1129. Wada S, Martin TJ, Findlay DM. Homologous regulation of the calcitonin receptor in
mouse osteoclast-like cells and human breast cancer T47D cells. Endocrinology 136:
26112621, 1995.
1131. Waldum HL, Sandvik AK, Brenna E, Petersen H. Gastrin-histamine sequence in the
regulation of gastric acid secretion. Gut 32: 698 701, 1991.
1132. Wallace JL, Cucala M, Mugridge K, Parente L. Secretagogue-specific effects of interleukin-1 on gastric acid secretion. Am J Physiol Gastrointest Liver Physiol 261: G559
G564, 1991.
1146. Wang TJ, Zhang F, Richards JB, Kestenbaum B, van Meurs JB, Berry D, Kiel DP, Streeten
EA, Ohlsson C, Koller DL, Peltonen L, Cooper JD, OReilly PF, Houston DK, Glazer NL,
Vandenput L, Peacock M, Shi J, Rivadeneira F, McCarthy MI, Anneli P, de Boer IH,
Mangino M, Kato B, Smyth DJ, Booth SL, Jacques PF, Burke GL, Goodarzi M, Cheung
CL, Wolf M, Rice K, Goltzman D, Hidiroglou N, Ladouceur M, Wareham NJ, Hocking LJ,
Hart D, Arden NK, Cooper C, Malik S, Fraser WD, Hartikainen AL, Zhai G, Macdonald
HM, Forouhi NG, Loos RJ, Reid DM, Hakim A, Dennison E, Liu Y, Power C, Stevens HE,
Jaana L, Vasan RS, Soranzo N, Bojunga J, Psaty BM, Lorentzon M, Foroud T, Harris TB,
Hofman A, Jansson JO, Cauley JA, Uitterlinden AG, Gibson Q, Jarvelin MR, Karasik D,
Siscovick DS, Econs MJ, Kritchevsky SB, Florez JC, Todd JA, Dupuis J, Hypponen E,
Spector TD. Common genetic determinants of vitamin D insufficiency: a genomewide association study. Lancet 376: 180 188, 2010.
1147. Wang W, Lu M, Balazy M, Hebert SC. Phospholipase A2 is involved in mediating the
effect of extracellular Ca2 on apical K channels in rat TAL. Am J Physiol Renal
Physiol 273: F421F429, 1997.
1148. Wang WH, Lu M, Hebert SC. Cytochrome P-450 metabolites mediate extracellular
Ca2-induced inhibition of apical K channels in the TAL. Am J Physiol Cell Physiol
271: C103C111, 1996.
1149. Wasserman RH, Corradino RA, Taylor AN. Vitamin D-dependent calcium-binding
protein. Purification and some properties. J Biol Chem 243: 3978 3986, 1968.
1150. Wasserman RH, Kallfelz FA, Comar CL. Active transport of calcium by rat duodenum in vivo. Science 133: 883 884, 1961.
1133. Walling MW, Rothman SS. Apparent increase in carrier affinity for intestinal calcium
transport following dietary calcium restriction. J Biol Chem 245: 50075011, 1970.
1151. Wasserman RH, Taylor AN. Vitamin D3-induced calcium-binding protein in chick
intestinal mucosa. Science 152: 791793, 1966.
1134. Walling MW, Rothman SS. Phosphate-independent, carrier-mediated active transport of calcium by rat intestine. Am J Physiol 217: 1144 1148, 1969.
1152. Wasserman RH, Taylor AN. Vitamin D-dependent calcium-binding protein. Response to some physiological and nutritional variables. J Biol Chem 243: 39873993,
1968.
266
1153. Watanabe S, Chey WY, Lee KY, Chang TM. Secretin is released by digestive products of fat in dogs. Gastroenterology 90: 1008 1017, 1986.
1154. Watson F, Kiernan RS, Deavall DG, Varro A, Dimaline R. Transcriptional activation of
the rat vesicular monoamine transporter 2 promoter in gastric epithelial cells: regulation by gastrin. J Biol Chem 276: 76617671, 2001.
1155. Watson PH, Fraher LJ, Hendy GN, Chung UI, Kisiel M, Natale BV, Hodsman AB.
Nuclear localization of the type 1 PTH/PTHrP receptor in rat tissues. J Bone Miner
Res 15: 10331044, 2000.
1156. Webb AR, Kline L, Holick MF. Influence of season and latitude on the cutaneous
synthesis of vitamin D3: exposure to winter sunlight in Boston and Edmonton will not
promote vitamin D3 synthesis in human skin. J Clin Endocrinol Metab 67: 373378,
1988.
1157. Weiss LA, Langenberg C, Barrett-Connor E. Ghrelin and bone: is there an association in older adults?: the Rancho Bernardo study. J Bone Miner Res 21: 752757, 2006.
1158. Weitkamp LR, Rucknagel DL, Gershowitz H. Genetic linkage between structural loci
for albumin and group specific component (Gc). Am J Hum Genet 18: 559 571, 1966.
1159. Wettschureck N, Lee E, Libutti SK, Offermanns S, Robey PG, Spiegel AM. Parathyroid-specific double knockout of Gq and G11 alpha-subunits leads to a phenotype
resembling germline knockout of the extracellular Ca2-sensing receptor. Mol Endocrinol 21: 274 280, 2007.
1160. Whalen EJ, Rajagopal S, Lefkowitz RJ. Therapeutic potential of beta-arrestin- and G
protein-biased agonists. Trends Mol Med 17: 126 139, 2011.
1130. Wada S, Udagawa N, Nagata N, Martin TJ, Findlay DM. Calcitonin receptor downregulation relates to calcitonin resistance in mature mouse osteoclasts. Endocrinology
137: 10421048, 1996.
1145. Wang TC, Koh TJ, Varro A, Cahill RJ, Dangler CA, Fox JG, Dockray GJ. Processing
and proliferative effects of human progastrin in transgenic mice. J Clin Invest 98:
1918 1929, 1996.
1169. Wolosin JM, Forte JG. Stimulation of oxyntic cell triggers K and Cl conductances
in apical H-K-ATPase membrane. Am J Physiol Cell Physiol 246: C537C545, 1984.
1182. Yamada T, Soll AH, Park J, Elashoff J. Autonomic regulation of somatostatin release:
studies with primary cultures of canine fundic mucosal cells. Am J Physiol Gastrointest
Liver Physiol 247: G567G573, 1984.
1183. Yamaguchi T, Chattopadhyay N, Kifor O, Brown EM. Extracellular calcium
[Ca2(o)]-sensing receptor in a murine bone marrow-derived stromal cell line
(ST2): potential mediator of the actions of Ca2(o) on the function of ST2 cells.
Endocrinology 139: 35613568, 1998.
1184. Yamaguchi T, Chattopadhyay N, Kifor O, Butters RR Jr, Sugimoto T, Brown EM.
Mouse osteoblastic cell line (MC3T3E1) expresses extracellular calcium (Ca2o)sensing receptor and its agonists stimulate chemotaxis and proliferation of
MC3T3-E1 cells. J Bone Miner Res 13: 1530 1538, 1998.
1185. Yamaguchi T, Chattopadhyay N, Kifor O, Ye C, Vassilev PM, Sanders JL, Brown EM.
Expression of extracellular calcium-sensing receptor in human osteoblastic MG-63
cell line. Am J Physiol Cell Physiol 280: C382C393, 2001.
1186. Yamauchi M, Yamaguchi T, Kaji H, Sugimoto T, Chihara K. Involvement of calciumsensing receptor in osteoblastic differentiation of mouse MC3T3E1 cells. Am J
Physiol Endocrinol Metab 288: E608 E616, 2005.
1187. Yang F, Brune JL, Naylor SL, Cupples RL, Naberhaus KH, Bowman BH. Human
group-specific component (Gc) is a member of the albumin family. Proc Natl Acad Sci
USA 82: 7994 7998, 1985.
1188. Yang F, Luna VJ, McAnelly RD, Naberhaus KH, Cupples RL, Bowman BH. Evolutionary and structural relationships among the group-specific component, albumin and
alpha-fetoprotein. Nucleic Acids Res 13: 8007 8017, 1985.
1189. Yang W, Friedman PA, Kumar R, Omdahl JL, May BK, Siu-Caldera ML, Reddy GS,
Christakos S. Expression of 25(OH)D3 24-hydroxylase in distal nephron: coordinate
regulation by 1,25(OH)2D3 and cAMP or PTH. Am J Physiol Endocrinol Metab 276:
E793E805, 1999.
1171. Wortsman J, Pak CY, Bartter FC, Deftos L, Delea CS. Pathogenesis of osteomalacia
in secondary hyperparathyroidism after gastrectomy. Am J Med 52: 556 564, 1972.
1190. Yang YX, Lewis JD, Epstein S, Metz DC. Long-term proton pump inhibitor therapy
and risk of hip fracture. JAMA 296: 29472953, 2006.
1172. Wrenn RW, Biddulph DM. Parathyroid hormone-induced calcium efflux from isolated renal cortical tubules: evidence for cyclic AMP mediation. Mol Cell Endocrinol
15: 29 40, 1979.
1191. Yao X, Karam SM, Ramilo M, Rong Q, Thibodeau A, Forte JG. Stimulation of gastric
acid secretion by cAMP in a novel alpha-toxin-permeabilized gland model. Am J
Physiol Cell Physiol 271: C61C73, 1996.
1173. Wright MJ, Sullivan RR, Gaffney-Stomberg E, Caseria DM, OBrien KO, Proctor DD,
Simpson CA, Kerstetter JE, Insogna KL. Inhibiting gastric acid production does not
affect intestinal calcium absorption in young, healthy individuals: a randomized,
crossover, controlled clinical trial. J Bone Miner Res 25: 22052211, 2010.
1192. Ye CP, Yamaguchi T, Chattopadhyay N, Sanders JL, Vassilev PM, Brown EM. Extracellular calcium-sensing-receptor (CaR)-mediated opening of an outward K channel in murine MC3T3-E1 osteoblastic cells: evidence for expression of a functional
CaR. Bone 27: 2127, 2000.
1174. Wu G, Burzon DT, di SantAgnese PA, Schoen S, Deftos LJ, Gershagen S, Cockett
AT. Calcitonin receptor mRNA expression in the human prostate. Urology 47: 376
381, 1996.
1193. Yergey AL, Abrams SA, Vieira NE, Aldroubi A, Marini J, Sidbury JB. Determination of
fractional absorption of dietary calcium in humans. J Nutr 124: 674 682, 1994.
1175. Wu S, Grieff M, Brown AJ. Regulation of renal vitamin D-24-hydroxylase by phosphate: effects of hypophysectomy, growth hormone and insulin-like growth factor I.
Biochem Biophys Res Commun 233: 813 817, 1997.
1176. Wuster C, Raue F, Meyer C, Bergmann M, Ziegler R. Long-term excess of endogenous calcitonin in patients with medullary thyroid carcinoma does not affect bone
mineral density. J Endocrinol 134: 141147, 1992.
1177. Wyatt MA, Jarvie E, Feniuk W, Humphrey PP. Somatostatin sst2 receptor-mediated
inhibition of parietal cell function in rat isolated gastric mucosa. Br J Pharmacol 119:
905910, 1996.
1178. Xu H, Zhao H, Tian W, Yoshida K, Roullet JB, Cohen DM. Regulation of a transient
receptor potential (TRP) channel by tyrosine phosphorylation. SRC family kinasedependent tyrosine phosphorylation of TRPV4 on TYR-253 mediates its response to
hypotonic stress. J Biol Chem 278: 11520 11527, 2003.
1179. Xu J, Henriksnas J, Barone S, Witte D, Shull GE, Forte JG, Holm L, Soleimani M.
SLC26A9 is expressed in gastric surface epithelial cells, mediates Cl/HCO3 exchange, is inhibited by NH4. Am J Physiol Cell Physiol 289: C493C505, 2005.
1199. Zaidi M, Chambers TJ, Gaines Das RE, Morris HR, MacIntyre I. A direct action of
human calcitonin gene-related peptide on isolated osteoclasts. J Endocrinol 115:
511518, 1987.
1180. Xu J, Song P, Miller ML, Borgese F, Barone S, Riederer B, Wang Z, Alper SL, Forte JG,
Shull GE, Ehrenfeld J, Seidler U, Soleimani M. Deletion of the chloride transporter
Slc26a9 causes loss of tubulovesicles in parietal cells and impairs acid secretion in the
stomach. Proc Natl Acad Sci USA 105: 1795517960, 2008.
1200. Zanello LP, Norman AW. Rapid modulation of osteoblast ion channel responses by
1alpha,25(OH)2-vitamin D3 requires the presence of a functional vitamin D nuclear
receptor. Proc Natl Acad Sci USA 101: 1589 1594, 2004.
1181. Xue Y, Fleet JC. Intestinal vitamin D receptor is required for normal calcium and
bone metabolism in mice. Gastroenterology 136: 13171327, e13111312, 2009.
267
1170. Woodrow JP, Sharpe CJ, Fudge NJ, Hoff AO, Gagel RF, Kovacs CS. Calcitonin plays
a critical role in regulating skeletal mineral metabolism during lactation. Endocrinology
147: 4010 4021, 2006.
1203. Zavros Y, Shulkes A. Cholecystokinin (CCK) regulates somatostatin secretion through both
the CCK-A and CCK-B/gastrin receptors in sheep. J Physiol 505: 811821, 1997.
1204. Zehnder D, Bland R, Chana RS, Wheeler DC, Howie AJ, Williams MC, Stewart PM,
Hewison M. Synthesis of 1,25-dihydroxyvitamin D3 by human endothelial cells is
regulated by inflammatory cytokines: a novel autocrine determinant of vascular cell
adhesion. J Am Soc Nephrol 13: 621 629, 2002.
1205. Zehnder D, Bland R, Williams MC, McNinch RW, Howie AJ, Stewart PM, Hewison
M. Extrarenal expression of 25-hydroxyvitamin d(3)-1 alpha-hydroxylase. J Clin Endocrinol Metab 86: 888 894, 2001.
1206. Zehnder D, Evans KN, Kilby MD, Bulmer JN, Innes BA, Stewart PM, Hewison M.
The ontogeny of 25-hydroxyvitamin D(3) 1alpha-hydroxylase expression in human
placenta and decidua. Am J Pathol 161: 105114, 2002.
1207. Zeng N, Athmann C, Kang T, Lyu RM, Walsh JH, Ohning GV, Sachs G, Pisegna JR.
PACAP type I receptor activation regulates ECL cells and gastric acid secretion. J Clin
Invest 104: 13831391, 1999.
1208. Zeng N, Kang T, Lyu RM, Wong H, Wen Y, Walsh JH, Sachs G, Pisegna JR. The
pituitary adenylate cyclase activating polypeptide type 1 receptor (PAC1-R) is expressed on gastric ECL cells: evidence by immunocytochemistry and RT-PCR. Ann
NY Acad Sci 865: 147156, 1998.
1209. Zeng N, Kang T, Wen Y, Wong H, Walsh J, Sachs G. Galanin inhibition of enterochromaffin-like cell function. Gastroenterology 115: 330 339, 1998.
1216. Zhao G, Simpson RU. Membrane localization, Caveolin-3 association and rapid
actions of vitamin D receptor in cardiac myocytes. Steroids 75: 555559,
2010.
1217. Zhong Y, Armbrecht HJ, Christakos S. Calcitonin, a regulator of the 25-hydroxyvitamin D3 1alpha-hydroxylase gene. J Biol Chem 284: 11059 11069, 2009.
1218. Zhou AT, Assil I, Abou-Samra AB. Role of asparagine-linked oligosaccharides in the
function of the rat PTH/PTHrP receptor. Biochemistry 39: 6514 6520, 2000.
1219. Zhou C, Lu F, Cao K, Xu D, Goltzman D, Miao D. Calcium-independent and
1,25(OH)2D3-dependent regulation of the renin-angiotensin system in 1alpha-hydroxylase knockout mice. Kidney Int 74: 170 179, 2008.
1220. Zhuang L, Peng JB, Tou L, Takanaga H, Adam RM, Hediger MA, Freeman MR.
Calcium-selective ion channel, CaT1, is apically localized in gastrointestinal tract
epithelia and is aberrantly expressed in human malignancies. Lab Invest 82: 1755
1764, 2002.
1221. Zhuang X, Adipietro KA, Datta S, Northup JK, Ray K. Rab1 small GTP-binding
protein regulates cell surface trafficking of the human calcium-sensing receptor.
Endocrinology 151: 5114 5123, 2010.
1222. Zierold C, Mings JA, DeLuca HF. Parathyroid hormone regulates 25-hydroxyvitamin
D(3)-24-hydroxylase mRNA by altering its stability. Proc Natl Acad Sci USA 98:
1357213576, 2001.
1211. Zhang JX, Fasciotto BH, Darling DS, Cohn DV. Pancreastatin, a chromogranin Aderived peptide, inhibits transcription of the parathyroid hormone and chromogranin A genes and decreases the stability of the respective messenger ribonucleic
acids in parathyroid cells in culture. Endocrinology 134: 1310 1316, 1994.
1212. Zhang W, Na T, Wu G, Jing H, Peng JB. Down-regulation of intestinal apical calcium entry
channel TRPV6 by ubiquitin E3 ligase Nedd42. J Biol Chem 285: 3658636596, 2010.
1224. Zornitzer AE, Bronner F. In situ studies of calcium absorption in rats. Am J Physiol
220: 12611266, 1971.
1213. Zhang Z, Sun S, Quinn SJ, Brown EM, Bai M. The extracellular calcium-sensing
receptor dimerizes through multiple types of intermolecular interactions. J Biol Chem
276: 5316 5322, 2001.
1225. Zuo Q, Claveau D, Hilal G, Leclerc M, Brunette MG. Effect of calcitonin on calcium
transport by the luminal and basolateral membranes of the rabbit nephron. Kidney Int
51: 19911999, 1997.
268
1210. Zeng N, Walsh JH, Kang T, Wu SV, Sachs G. Peptide YY inhibition of rat gastric
enterochromaffin-like cell function. Gastroenterology 112: 127135, 1997.
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