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The endocrine (or) ductless glands secrete hormones directly into the blood
stream
Local hormones
Local hormones act mainly in the tissues and sites in which they are
produced eg. Eicosanoids, endothelin, nitric oxide, histamine etc
Tropic hormones
They also promote the synthesis of hormones and increase the vascularity
and the growth of the target gland or tissue
Endocrine hormone
Paracrine hormone
Autocrine hormone
lipid derivatives
Steroids: --------
Fatty acid-------
prostaglandin
Retinols---------
retinoic acid
When circulating hormone level is increased, the hormone can control its
synthesis by negative feedback regulation When circulating hormone level is
decreased, the hormone can control its synthesis by positive feed forward
regulation
7.Target cell
It is the type of cell that able to recognize specific hormone due to
presence of specific receptor
Target cells must distinguish not only between different hormones but also
between a given hormone and related molecules
8. Receptors
Receptors are proteins that bind a specific extracellular signaling molecule
(ligand) and initiate a response in the cell. They are located on the cell
surface or in the cytosol/ nucleus of the target cell
Receptors have very high specificity and affinity to its hormone. Hormone
receptors are protein in nature
RECEPTORS
The action of hormone starts by binding to cell associated recognition molecule
called receptors. Receptors are proteins that bind a specific extracellular signal
molecule (ligand) and initiates a response in the cell. They are protein or glycoprotein in
nature. There are 2 types of receptors
1. Intracellular receptors
2. Cell surface receptors.
1) Intracellular receptors
Receptors for lipophilic (steroid) hormones are present in the cytosol or nucleus
of target cells. Their action is by mediating gene expression. Steroid hormone receptors
have several functional domains--1.
2.
3.
4.
5.
transducer and generates signals that alter the behavior of target cell. Cell surface
receptors have 3 functional domains--1. Hormone binding domain
2. Transmembrane domain
3. Signal transduction domain
Most cell surface receptors belong to one of the three classes. They are
1. Ion-channeled linked receptors
2. G-protein linked receptors
3. Enzyme linked receptors
(1) Ion-channeled linked receptors
Also known as transmitter gated ion channels.
These receptors are concentrated in post synaptic cell membrane.
Neurotransmitters transiently open or close the ion channel and alter the
permeability of cell membrane.
They belong to homologous multi-pass trans-membrane proteins.
E.g, receptor for acetylcholine
(2)G-protein linked receptors
They act indirectly to regulate the activity of separate membrane bound target
protein which can be an enzyme or ion channel.
The interaction between the receptor and target protein is mediated by G-protein.
They belong to homologous seven pass trans-membrane protein.
Example receptors for catecholamine
(3)Enzyme linked receptors
These receptors either function as enzymes or associated with enzymes.
They are heterogenous single pass trans-membrane protein.
Example , receptor for insulin
The number of receptors in cells are not static , they are dynamic in nature. When
the hormone is present in excess, the number of active receptor is decreased by
internalization, desensitization and repression(down regulation). If the amount of
hormone is decreased, the number of receptor will increase by induction(up regulation)
Biomedical importance.
Androgen receptor agonist enhances the development of lean muscle mass.
Estrogen receptor antagonists (tamoxifen) are used in treatment of breast cancer.
Glucocorticoids
Mineralocorticoids
Retinoic acid
angiotensin II
2+
Antiduretic hormone
1 adrenergic catecholamines
Acetylcholine
insulin
Erythropoietin
Growth hormone
Cell signaling
Signaling molecules
Signaling molecules can generate specific response in its target cell to adapt the
changes in its environment. Signaling molecules are
1.
2.
3.
4.
5.
6.
7.
Signal transduction
Signal transduction is the process by which the message carried by signaling
molecule is accepted by (specific cell associated molecule called) receptor, then
transmitted via intracellular modulator and generate the appropriate responses of the
cells
Mechanisms of Action of Hormones/ General mechanism of cell signaling
Depend on type of receptors which in turns on solubility, hormones can be
divided into lipid soluble hormone & water soluble hormone
1. Mechanism of lipophilic signaling molecules
2. Mechanism of hydrophilic signaling molecules
A. that use ion channel linked receptors
B. that used G protein linked receptors
C. that used enzyme linked receptor
Because of lipid soluble in nature, free hormone transverses cell membrane and
binds to intracellular receptors (in cytoplasm or nucleus) of target cells.
HRC moves into the nucleus and binds to hormone response element (HRE)
of a particular gene & activate or inactivate specific gene.
Hormones cannot pass through the cell membrane. So they bind to cell surface
receptor(membrane receptor). Their mechanism is mediated by intracellular
signals (second messengers). Hormones act as the first messenger that carry
information from endocrine gland to target cell and 2 nd messenger carry
information from cell membrane to metabolic processes.
- Gs (s)
ANP or NO signaling
Insulin, EGF & IGF-1 receptors have intrinsic tyrosine kinase activity. Binding of
hormone to receptor causes dimerization and cross phosphorylation on tyrosine
residue.
2nd Messengers are ----1)cAMP 2)cGMP 3)IP3 (inositol 1,4,5 triphosphat) 4) DAG
(1,2 diacyl glycerol)(5) Ca++
1. cAMP(cyclic adenosine monophosphate)
Formation --- when some hydrophilic hormone bind to G-protein linked receptor,
membrane bound G protein is activated which then activate membrane bound
adenylate cyclase that catalyzed the conversion of ATP to cAMP. Increased cAMP
activates cAMP dependent protein kinase(PKA) which further phosphorylate target
proteins and initiate cellular responses. In some animal cells an increase in cAMP
activates the transcription of specific gene through cAMP response element binding
(CREB) protein. Hormones such as ADH, glucagon, epinephrine(-adrenergic),etc exert
their action via cAMP. cAMP is degraded to 5 AMP by phosphodiesterase enzyme.
Calcium and calmodulin (Ca++ binding protein) complex activate Ca-M kinase &
DAG activate protein kinase C
CaM-kinase and PKC also phosphorylate target proteins and regulate the cellular
functions
G-protein is inactive when GDP is bound to subunit and active when GTP is
bound to subunit.
When hormone binds to a G-protein linked receptor, the receptor changes its
conformation and switches to active form ( to eject their GDP and replaces it
with GTP)
The intrinsic GTPase activity of subunit converts the GTP to GDP which
inactivates the protein.
- Gs (s)
Gs & Gi System
Gq system
The responses are rapidly turned off by removal of external signal and break
down of GTP to GDP by GTPase
Biomedical Importance
ras proteins (member of GTPase family ) that cycle between GTP and GDP forms
Insulin has no plasma carrier protein. Metabolism occurs in liver (50%), kidney and
placenta.2 enzymes systems degrade insulin,1. insulin specific protea 2. glutathione
insulin transhydrogenase
Mechanism of insulin action
1.
Ther
e is
conf
orma
tiona
chan
ge
of
the
rece
ptor
2.
When
rece
ptors
cross
-link
and
form
micr
oagg
rega
tes
3.
Rece
ptor
is
Phosphorylated IRS
inter
These proteins are docking proteins, kinases and phosphatases. The effect of
insulin on membrane transport, enzyme activity, gene expression and growth are
well known.
naliz
ed
and
dow
n
regul
ated
4.
One
Adipose tissue inhibit
lipolysis
or
more
sign
als
Activate lipolysis
are
BIOSYNTHESIS OF HORMONES
gene
Biosynthesis of amino acid
derivative hormones
rate
Catecholeamine; - dopa,
dopamine, norepinephrine and
epinephrine
Thyroid hormones
5. Secretion
1. Concnetration of iodide
Concentrate iodide against a strong electrochemical gradient
Energy-dependent process and linked to ATPase-dependent Na +/K+ pump
(thyroidal I- pump)
The activity of pump is controlled by TSH
The ratio of iodide in thyroid to iodide in serum (T:S) ratio in human on a
normal iodine diet is about 25. The transport mechanism is inhibited by 2
classes
Perchlorate , Perrhenate and pertechnetate compete with iodide
Thiocyanate is a competitive inhibitor of iodide transport
2. Oxidation of iodide
Thyroid is only tissue that can oxidize iodide
An obligatory step in iodide organification and thyroid hormone biosynthesis
Involved a heme-containing peroxidase and H2O2
Iodide oxidation is inhibited by thiourea drugs
3. Iodiantion of tyrosyl residues
Oxdized iodide reacts with the tyrosyl residues in thyroglobulin. This reaction
is catalyzed by thyroperoxidase
3 position of aromatic ring is iodinated first and then 5 position to form MIT
(monoiodotyrosine) and DIT (diiodotyrosine) respectively, catalyzed by
thyroperoxidase
Thyroglobulin is precursor of T3 and T4
4. Coupling of iodotyrosyls
Coupling of 2 DIT molecules to form T4
Coupling of one MIT and one DIT to form T3, catalyzed by thyroperoxidase
Thiourea also inhibit coupling
About 70% of iodide in thyroglobulin exists as MIT and DIT and 30% exist in
T4 and T3
5. Secretion
iodinated thyroglobulin are stored in extracellular colloid
After TSH or cAMP stimulation, there is marked increase of microvilli on
apical membrane
Microtubule-depedent process entraps thyroglobulin and pinocytose into the
follicular cell
Phagosome fuse with lysosomes to form phagolysosomes
Proteases and peptidases hydrolyzes thyroglobulin and T3 and T4 are
discharged from basal portion of cell into blood. About 50 g of thyroid
hormone is secreted each day
Mechanism of action of thyroid hormone
TH binds to intra nuclear receptor and HR complex binds to thyroid hormone
response element binding region(TRE) of DNA and regulate gene expression.TH
enhances the synthesis of sodium-potassium ATPase pump.
Biosynthesis of hormones of adrenal medulla
Catecholamines synthesized in chromaffin cells of adrenal medulla
Catecholamine (dopamine, norepinephrine and epinephrine)
80% is epinephrine
zona glomerulosa
zona fasciculata
Gonads are bifunctional organs, produce germ cells and the sex hormones
Testes produce spermatozoa and testosterone
Testicular androgen are synthesis by the Leydig cells
Immediate precursor of gonadal steroid is cholesterol
Pregnenolone to testosterone require actions of 5 enzyme and 2 pathways
5 (or) dehydroepiandrosterone
ACTIONS OF CALCITRIOL
Effects on intestine
Increases calcium absorption from intestine by increasing the synthesis of
calbindin D
Effects on kidney
Facilitates Ca++ reabsorption in the kidneys
Effects on bone
It mobilizes Ca++ and increase the number of osteocalsts
stimulates osteoblast to produce osteoclastic resorption stimulating activity
(ORSA) and neutral protease
ORSA stimulates osteoclast and protease digest unmineralized bone
Calcitonin
peptide hormone (32 amino acids),,, secreted from parafollicular C cells of
thyroid gland.
Mechanism of action
By binding G-protein linked cell surface receptor and increases cAMP level.
Action of Calcitonin
Lowers circulating calcium and phosphate levels. It inhibits action of osteoclast
and decreases bone resorption. It Increases excretion of calcium in the urine.