Endogenous ligands part 2

EICOSANOIDS
20-carbon molecules derived from arachidonic acid oxygenation.
• Prostanoids
- prostaglandins (PGs)
- thromboxanes (Txs)
• Leucotrienes (LTs)
• Lipoxins
 Prostaglandins have two derivatives:
• Prostacyclins and thromboxanes.
• Prostacyclins are powerful locally acting vasodilators and
inhibit the aggregation of blood platelets. Through their role in
vasodilation, prostacyclins are also involved in inflammation.
They are synthesized in blood vessels, regulating the
contraction of smooth muscle tissue.
• Conversely, thromboxanes (produced by platelet cells) are
vasoconstrictors and facilitate platelet aggregation. Their name
comes from their role in clot formation (thrombosis).
Functions of PGs
Bradykinins
• Bradykinins ,an endogenous vasodilator nonapeptide, (formed of nine
amino acid residues),released from plasma globulins called
kininogens.
• Two types of kininogens (alpha-globulin), a high molecular weight
(HMW) form present in plasma and a low molecular weight (LMW)
form present in tissues.
Synthesis of bradykinin
Bradykinin receptors
• The B2 receptor activates PLA2 and PLC via interaction with distinct G proteins.
Kinin-induced PLC activation through Gq activates the IP3–Ca2+ pathway,
stimulating PKC activity and also enhancing NO synthesis by eNOS/NOS3.
• Bradykinin activates the pro-inflammatory transcription factor NF-κB through
Gαq and βγ subunits and also activates the MAP kinase pathway. Coupling of
activated B2 receptors to Gi leads to PLA2 activation and the liberation
inflammatory mediators and vasodilator PGs and prostacyclin
• B1 receptors also couple through Gq and Gi to activate many of the
same signal transduction pathways as the B2 receptor.
• However, B1 receptor activation enhances NO production by
stimulation of the inducible nitric oxide synthase (iNOS) rather than
eNOS.
Renin angiotensin system
• The renin-angiotensin system plays role in regulation of the
volume, pressure, and electrolyte composition of blood salt
homeostasis
• Renin is a proteolytic enzyme that is produced by the kidneys.
• Renal RAS is salt sensitive, acts on a plasma protein to catalyze
the formation of the actual pressor substance called
angiotensin and the plasma protein, angiotensinogen.
RAS components
• First mechanism of renin release is that Sodium depletion
upregulates nNOS and COX-2 in the macula densa to enhance
production of prostaglandins (PGs). PGs and catecholamines
stimulate cAMP production and thence renin release from the
juxtaglomerular cells.
• Increased NaCl transport depletes ATP and increases
adenosine (ADO) levels.
• Adenosine diffuses to the juxtaglomerular cells and inhibits
cAMP production and renin release via Gi-coupled A1
receptors.
• The second mechanism controlling renin release is the
intrarenal baroreceptor pathway via stretch-activated ion
channels, release of renal prostaglandins.
• The third mechanism, the β adrenergic receptor pathway, is
mediated by the release of norepinephrine from
postganglionic sympathetic nerves; activation of β1 receptors
on juxtaglomerular cells enhances renin secretion.
RAS components
Angiotensin II functions
Endogenous Opioids
• Natural agonists for the opioid receptors
• Commonly known as endorphins (short for endogenous
morphine)
• Types of endorphins:
• Endorphins (mu opioid receptors)
• Endormorphins
• Enkephalins (delta opioid receptors and mu opioid receptors)
• Dynorphins (kappa receptors)
• Nociceptin; nociceptin receptor (NOP, ORL-1)
 Endogenous Opioids: MoA
• Neuropeptides that modulate neurotransmitter action
• Mechanism of Action:
• Produced from pro-hormones: pro-opiomelanocortin (β-endorphin), pro-
enkephalin and pro-dynorphan
• Released from the synapse and directly stimulate opioid receptors on the pre-
and postsynaptic membranes
• Each binds a different opioid receptor: β-endorphin and endomorphins (μ),
enkephalins (δ), dynorphins (κ)
• Rapidly degraded peptidases
Receptor Subtypes Functions

delta (δ) δ1, δ2 Analgesia, antidepressant effects, convulsant effects, physical

DOR dependence. may modulate μ-opioid receptor-mediated
OP1 respiratory depression

kappa (κ) κ1, κ2, κ3 analgesia, anticonvulsant effects, depression,

KOR dissociative/hallucinogenic effects, diuresis, sedation
OP2

mu (μ) μ1, μ2, μ3 μ1: analgesia, physical dependence

MOR μ2: respiratory depression, miosis, euphoria, reduced GI motility
OP3 μ3: possible vasodilation

Nociceptin rs. ORL1 Anxiety, depression, appetite, development of tolerance to μ-

NOR opioid agonists
OP4

zeta (ζ) tissue growth, embryonic development, regulation of cancer cell

ZOR proliferation
Opioid effects
Released by pituitary gland and hypothalamic neurons in response to pain, stress,
exercise, and labour & delivery
Numerous effects on the body; some examples include:
• Act relieve pain and anxiety
• Also associated with feelings of euphoria, increased appetite, and enhancement
of the immune response
• Responsible for the so-called “runner’s high”
• Increased release during long, strenuous exercise
• Results in sense of euphoria & increased pain threshold
• Play a role in social bonding
Bombesin
• Bombesin has two homologs, called neuromedin B and gastrin-
releasing peptide.
• It stimulates gastrin release from G cells. It activates three different G-
protein-coupled receptors
• Bombesin receptors are activated by the endogenous ligands
gastrin-releasing peptide, neuromedin B, neuromedin C.
• These receptors couple primarily to the Gq/11 family of G
proteins. Each of these receptors is widely distributed in the
CNS and peripheral tissues.
• Activation of BB1 and BB2 receptors causes a wide range of
physiological actions, including the stimulation of normal and
neoplastic tissue growth, smooth-muscle contraction, appetite
and feeding behavior, secretion glucose and insulin regulation,
metabolic homeostasis, feeding and many central nervous
system effects.
Neuromedin B
• Neuromedin B (NMB) is a bombesin-related peptide in
mammals.
• It is present in human central nervous system and
gastrointestinal tract
• NMB acts by binding to its high affinity cell surface receptor,
neuromedin B receptor (NMBR)
• Neuromedin regulates the following functions:
 exocrine and endocrine secretions
 cell growth
 body temperature
 blood pressure and glucose level
Neuromedin B receptor activation
Neurotensin
• Neurotensin is a 13 amino acid neuropeptide
• Regulation of luteinizing hormone and prolactin release
• Interaction with the dopaminergic system.
• Distributed in CNS, (hypothalamus, amygdala and nucleus
accumbens). It induces analgesia, hypothermia and increased
locomotor activity.
• In the periphery, neurotensin is found in enteroendocrine cells
of the small intestine, where it leads to secretion and smooth
muscle contraction
 Hormones

• Steroidal hormones
• Two classes: corticosteroids (typically made in the adrenal cortex) and
sex steroids (typically made in the gonads or placenta)
• Non steroidal hormones e.g. peptide hormones
Release of hormones
Steroid hormones
• Steroid hormones are manufactured from cholesterol
• Cholesterol is manufactured mainly in the liver, and
released into the bloodstream. Most steroid
hormones are produced in the adrenal gland and in
the gonads (testes and ovaries).
1. Corticosteroids
• Corticosteroids produced in the adrenal cortex
• Two main classes; glucocorticoids (GR) and mineralocorticoids
(MR)
• Glucocorticoids such as cortisol affect carbohydrate, fat, and
protein metabolism, and have anti-inflammatory,
immunosuppressive, anti-proliferative, and vasoconstrictive
effects.
• Mineralocorticoids such as aldosterone are primarily involved
in the regulation of electrolyte and water balance by
modulating ion transport in the epithelial cells of the renal
tubules of the kidney.
2. Sex steroids
Sex steroids include:
• Androgens e.g. Testosterone (AR)
• Estrogens e.g. Estradiol (ER)
• Progestogens e.g. Progesterone (PR)

• Testosterone plays a key role in the development of male

reproductive tissues, promoting secondary sexual
characteristics such as increased muscle and bone mass, and
the growth of body hair.
• In addition, Prevention of osteoporosis.
• Estrogen is important in the regulation of the estrous and menstrual female
reproductive cycles.
• Essential for the development and maintenance of female reproductive tissues
• Also has important effects in many other tissues including bone, fat, skin, liver,
and the brain.
Estrogen receptors
Progestin receptors
• The binding of progesterone activates the progestin receptor,
and a transduction pathway characteristic of Gi proteins
occurs; deactivation of adenyl cyclase reduces cytosolic cAMP
levels. This change in cAMP concentration, in turn, activates
the MAP kinase cascade.
 Vitamin D
• steroid hormone, synthesized starting in the skin
• requires exposure to UV rays to begin process
• helps regulate blood calcium and phosphate levels
• increases release of calcium into blood from bone
• increases reabsorption of calcium in kidney and absorption of calcium
in duodenum
Non Steroid Hormones
• Protein type hormones may actually be amino acids, peptides
(linked chains of amino acids) or complete proteins. They can
usually not cross a cell membrane. Instead, they bind with a
receptor on the surface of a target cell.
• The combination of nonsteroid hormone and receptor
activates enzymes in the cell membrane, which produce a
compound that acts as a second messenger. Some common
second messengers include cAMP, calcium, or other enzymes
from within the cell.
Mechanism of action
Hormones of the Anterior Pituitary Gland
Thyroid Stimulating Hormone (TSH)
• Stimulates the production and release of thyroxin by the
thyroid gland.
 Adrenocorticotropin (ACTH)
• Stimulates production and release of hormones from the
cortex (outer layer) of the adrenal glands
 Prolactin (PRL)
• Stimulates development of mammary gland tissue and milk production after a
female gives birth
Human Growth Hormone (HGH)
• Also referred to as somatotropin . Increases absorption of calcium, which results
in growth of bone and cartilage tissue; also stimulates protein synthesis and lipid
metabolism
 Follicle Stimulating Hormone (FSH)
• In females, stimulates the development of egg cells in the ovaries. In males,
controls development of sperm cells in the testes
Leutinizing Hormone (LH)
• Causes the release of egg cells from the ovaries in females In both males and
females, it controls the production of sex hormones
Posterior pituitary gland
Antidiuretic Hormone (ADH)
• Also called vasopressin. Regulates sodium levels in the
bloodstream; stimulates vasoconstriction (constriction of
severed arteries to reduce blood loss)
• Increases water permeability of the kidney's collecting duct
and distal convoluted tubule by inducing translocation of
aquaporin-CD water channels
Oxytocin
• Oxytocin is a human peptide hormone that is used as
a medication to facilitate childbirth.
• It acts on oxytocin receptor, OXTR (G-protein coupled
receptor family, specifically Gq)
• It is expressed by the myoepithelial cells of the
mammary gland, and in both the myometrium and
endometrium of the uterus at the end of pregnancy.
Thyroid hormones
Thyroxine (T3)
• Nonsteroid hormone
• Increases base metabolic rate, especially in the
Skeletal muscle, heart, liver, and kidneys
• Necessary for normal mental and physical
development
Thyroid hormone synthesis
 Calcitonin
• Produced primarily by the parafollicular cells (also known as C-
cells) of the thyroid
• Increases rate of calcium deposit in bone cells
• Increases calcium excretion in the kidneys
• Decreased calcium levels in the blood, opposes the effects of
parathyroid hormone
• Calcitonin receptor, found on osteoclasts, and in the kidney
and regions of the brain, is coupled by Gs to adenylate cyclase
and thereby to the generation of cAMP in target cells.
 Parathyroid Hormone (PTH)
• Causes bone tissue to release calcium into the blood
• Promotes Vitamin D synthesis, which:
• Increases calcium reabsorption by the kidneys
• Increases calcium absorption by small intestine
• Result: increased calcium levels in the blood
The Pancreas
Insulin
• triggers the liver to absorb glucose from the blood,
and store it as glycogen
• increase fat tissue absorption of glucose, fatty acids,
and amino acids
• stimulates protein synthesis and tissue growth
• suppresses glucose metabolism in liver and muscle
cells
Glucagon
• triggers the liver to convert glycogen to glucose, and
release glucose into the blood
Insulin receptor
Glucagon receptor
The Pineal Gland
Melatonin
• follows a cyclic pattern of rising and falling (Circadian
rhythm)
• Induces feeling of sleepiness
The Thymus Gland
Thymosin
• normally present only until puberty
• stimulates maturation of lymph cells into T cells
Gastrin
• Gastrin is a peptide hormone that stimulates secretion of gastric acid (HCl) by the
parietal cells of the stomach and aids in gastric motility. It is released by G cells in
the pyloric antrum of the stomach, duodenum, and the pancreas.
• Gastrin binds to cholecystokinin B receptors to stimulate the release of
histamines in enterochromaffin-like cells, and it induces the insertion of K+/H+
ATPase pumps into the apical membrane of parietal cells (which in turn increases
H+ release into the stomach cavity)
Secretin
• Secretin is a peptide hormone produced in the S cells
of duodenum.
• Secretin helps regulate the pH of the duodenum by
(1) inhibiting the secretion of gastric acid from the
parietal cells of the stomach and (2) stimulating the
production of bicarbonate from the centroacinar cells
and intercalated ducts of the pancreas.
• It also stimulates bile production by the liver.
Secretin
Cholecystokinin
• Cholecystokinin is a peptide hormone, stimulate digestion of
fat and protein.
• Synthesized and secreted by enteroendocrine cells in the
duodenum
• Its presence causes the release of digestive enzymes and bile
from the pancreas and gallbladder, respectively
• Two receptors that bind cholecystokinin:
1. The CCKA receptor is found abundantly on pancreatic acinar
cells.
2. The CCKB receptor, which also functions as the gastrin
receptor, is the predominant form in brain and stomach.
3. Both receptors are have seven transmembrane domains
typical of G protein-coupled receptors
Motilin
• Motilin is a 22 amino acid peptide secreted by
endocrinocytes in the mucosa of the proximal small
intestine.
• Motilin participates in controlling the pattern of
smooth muscle contractions in the upper
gastrointestinal tract.
• Motilin is secreted into the circulation during the
fasted state. These bursts of motilin related to the
onset of "housekeeping contractions", which sweep
the stomach and small intestine clear of undigested
material (also called the migrating motor complex).
Ghrelin
Ghrelin is synthesized as a preprohormone, then proteolytically
processed to yield a 28-amino acid peptide.
• Cells within the anterior pituitary bear a receptor , when
activated, stimulates secretion of growth hormone - that
receptor was named the growth hormone secretagoue
receptor(GHS-R). The natural ligand for the GHS-R was ghrelin.
• Presence of ghrelin receptors in areas of the hypothalamus
involved in appetite regulation.
• At least two major biologic activities have been ascribed to
ghrelin:
• Stimulation of growth hormone secretion
• Regulation of energy balance: ghrelin functions to increase
hunger though its action on hypothalamic feeding centres.
• Other effects of ghrelin include stimulating gastric emptying
and having a variety of positive effects on cardiovascular
function (e.g. increased cardiac output).
VASOACTIVE INTESTINAL PEPTIDE
• VIP is structurally related to secretin.
• It has shown to be a potent vasodilator, widely distributed in
the peripheral and central NS.
• VIP seems to induce:
• smooth muscle relaxation (lower oesophageal sphincter,
stomach, gallbladder)
• stimulate secretion of water into pancreatic juice and bile
• cause inhibition of gastric acid secretion and absorption from
the intestinal lumen.
Leptin
• Leptin is a hormone made by adipose cells that helps to
regulate energy balance by inhibiting hunger.
• Leptin is opposed by the actions of the hormone ghrelin, the
"hunger hormone".
• Both hormones act on receptors of the hypothalamus to
regulate appetite to achieve energy homeostasis
• Leptin interacts with six types of receptors. Ob-Rb is the only
receptor isoform that can signal intracellularly via the Jak-Stat
and MAPK signal transduction pathways and is present in
hypothalamic nuclei
Ionic Milieu
• A relatively small number of drugs act by affecting the ionic milieu of blood,
urine, and the GI tract.
• Ionic milieu includes ion pumps and transporter proteins, many of which are
expressed only in specialized cells of the kidney and GI system.
• Drug effects on many of these receptors can have effects
throughout the body due to changes in blood electrolytes and
pH. For instance, most of the diuretics (e.g., furosemide,
chlorothiazide, amiloride) act by directly affecting ion pumps
and transporters in epithelial cells of the nephron that increase
the movement of Na+ into the urine, or by altering the
expression of ion pumps in these cells (e.g., aldosterone).
• Another therapeutically important target is the H+,K+-ATPase
(proton pump) of gastric parietal cells. Irreversible inhibition of
this proton pump by drugs such as esomeprazole reduces
gastric acid secretion by 80-95% and is a mainstay of therepy
for peptic ulcer.
Seven basic mechanisms for transmembrane transport of solutes.
1: convective flow in which dissolved solutes are "dragged" by
bulk water flow
2: simple diffusion of lipophilic solute across membrane;
3: diffusion of solute through a pore
4: transport of solute by carrier protein down electrochemical
gradient
5: transport of solute by carrier protein against electrochemical
gradient with ATP hydrolysis providing driving force
6 and 7: cotransport and countertransport, respectively, of
solutes, with one solute traveling uphill against an
electrochemical gradient and the other solute traveling down
an electrochemical gradient.
General Mechanism of Renal Epithelial Transport
Renal tubular transport
• 1. Na+, K+–ATPase (sodium pump) in the basolateral
membrane hydrolyzes ATP, which results in the transport of
Na+ into the interstitial spaces, the movement of K+ into the
cell. Although other ATPases exist in selected renal epithelial
cells and participate in the transport of specific solutes (e.g.,
Ca2+–ATPase and H+–ATPase).
• 2. Symporters (e.g., Na+–glucose, Na+–H2PO4–, and Na+–
amino acid) are involved in cotransport of various solutes
against their electrochemical gradients out of the tubular
lumen into the cell.
• Also, antiporters (e.g., Na+–H+) move Na+ out of and some
solutes into the tubular lumen.
Proton pumps
• Physiological agonists and their respective membrane
receptors include acetylcholine (ACh), gastrin, cholecystokinin
receptor 2 (CCK2); histamine (HIST), H2 rs; and prostaglandin
E2 (PGE2), EP3 receptor mimics the proton pumps for HCl
production.
• NSAIDs can induce ulcers via inhibition of cyclooxygenase
• Gastrin stimulates acid secretion indirectly by inducing the
release of histamine by ECL cells; a direct effect on parietal
cells also plays a lesser role.
Proton pumps