HORMONES, RECEPTORS, AND COMMUNICATION BETWEEN CELLS

MALIK ALQUB MD. PHD.

General principles

Selected hormones & their functions

Insulin Pancreas Controls blood-sugar level and storage of glycogen.

Glucagon Pancreas Stimulates conversion of glycogen to glucose;

raises blood sugar level. Oxytocin Pituitary gland Stimulates contraction of the uterine muscles and

secretion of milk by the mammary glands.

Vasopressin Pituitary gland Controls water excretion by the kidneys; stimulates

contraction of the blood vessels.

Growth hormone Pituitary gland Stimulates growth.

Adrenocorticotrophic Pituitary gland Stimulates the adrenal cortex, which,in turn,releases

hormone (ACTH) several steroid hormones.

Prolactin Pituitary gland Stimulates milk production by the mammary glands

after birth of baby.

Epinephrine Adrenal glands Stimulates rise in blood pressure, acceleration of

heartbeat, decreased secretion of insulin, and increased blood sugar.

Hormones, Receptors, and Communication Between Cells

Intracellular receptors lipid soluble hormones

Steroid hormones, vitamin D, retinoids, thyroxine

Bind to intracellular protein receptors This binds to regulatory elements by a gene Alters the rate of gene transcription

Induces or represses gene transcription

Hormones, Receptors, and Communication Between Cells

Intracellular Receptors

Hormones, Receptors, and Communication Between Cells

Cell-surface receptors Water soluble hormones

Peptide hormones (insulin), catecholamines, neurotransmitters

Three class of cell-surface receptors Ligand-Gated Receptors Catalytic Receptors G Protein-linked Receptors

Ligand-gated receptors

Binding of a ligand (often a neurotransmitter) affects flow of ions in/out of cell

Gamma-amino butyric acid (GABA) binds and opens chloride channels in the brain Valium (anti-anxiety drug) reduces the amount

of GABA required to open the chloride channels

Gated Channels

Voltage Gated Ligand Gated

Catalytic receptors

Binding of hormone activates tyrosine kinase on receptor which phosphorylates certain cellular proteins

Insulin receptor is a catalytic receptor with TYR Kinase activity

Insulin Signal Transduction CascadesInsulin Promotes Cell growth, Glucose uptake and

storage Insulin Receptors (IR) bind 2 insulin peptide with 2 α

chains β chains (auto-)phosphorylate each other P- β subunits now active tyrosine kinases

Active RTK initiates a signal transduction cascade RTK phosphorylates Insulin Receptor Substrate-1

(IRS-1) Adaptor proteins Grb2 and Sos bind to P-Tyr-

IRS-1 via SH2 domain Sos activates Ras GTPase

Ras.GTP activatesProtein Kinase Cascade

Many enzymes are regulated by covalent attachment of phosphate, in ester linkage, to the side-chain hydroxyl group of a particular amino acid residue (serine, threonine, or tyrosine).

H3N+ C COO

CH OH

CH3

H

threonine (Thr)

H3N+ C COO

CH2

OH

H

serine (Ser)

A protein kinase transfers the terminal phosphate of ATP to a hydroxyl group on a protein.

A protein phosphatase catalyzes removal of the Pi by hydrolysis.

P r o te in O H + A T P P r o te in O P

O

O

O

+ A D P

P i H 2 O

P r o te in K in a s e

P r o te in P h o s p h a ta s e

Protein kinases and phosphatases are themselves regulated by complex signal cascades. For example: Some protein kinases are activated by Ca++-

calmodulin. Protein Kinase A is activated by cyclic-

AMP (cAMP).

P r o te in O H + A T P P r o te in O P

O

O

O

+ A D P

P i H 2 O

P r o te in K in a s e

P r o te in P h o s p h a ta s e

G-protein-linked receptors

Binding of hormone activates an enzyme via a G-protein communication link.

The enzymes produces intracellular messengers cAMP diacylglycerol (DAG))

Intracellular Messengers:Signal Transduction Pathways

Cyclic AMP (cAMP) Diacylglycerol (DAG) & Inositol

Triphosphate (IP3) Cyclic GMP (cGMP)

G-Protein-Linked Receptors:

Two types of G-Proteins

Stimulating G protein (Gs)

Activate adenylate cyclase Inhibitory G proteins (Gi)

Inhibit adenylate cyclase

G Proteins

G proteins are trimers Three protein units

Alpha Beta gamma

Alpha proteins are different in Gs and Gi

Both have GTPase activity Alpha proteins modify adenylate cyclase

activity AC stimulated by Alpha(s) when activated by a

hormone AC Inhibited by Alpha(I) when activated by other

hormones

a & g subunits have covalently attached lipid anchors that bind a G-protein to the plasma membrane cytosolic surface.

Adenylate Cyclase (AC) is a transmembrane protein, with cytosolic domains forming the catalytic site.

AC

hormone signal outside GPCR plasma membrane

GTP GDP ATP cAMP + PP i

cytosol

GDP GTP

The asubunit of a G-protein (Ga) binds GTP, & can hydrolyze it to GDP + Pi.

Family of G Proteins

Binding of hormones to receptors causes: GTP to displace GDP Dissociation of alpha

protein from beta and gamma subunits

activation of the alpha protein

Inhibition or activation of adenylate cyclase

GTPase gradually degrades GTP and inactivates the alpha protein effect (clock)

The cAMP Signal Transduction Pathway

cAMP – intracellular messenger Elevated cAMP can either activate or inhibit

regulatory enzymes cAMP activates glycogen degradation cAMP inhibits glycogen synthesis

[cAMP] affected by rates of synthesis and degradation Synthesis by adenylate cyclase Degradation by phosphodiesterase

Stimulated by insulin Inhibited by caffeine

Activation of Protein Kinase A by cAMP

Protein kinase A Activates or inhibits several enzymes of CHO

and Lipid metabolism Inactive form: regulatory+catalytic subunits

associated Active form: binding of cAMP disassociates

subunits

1. Ga hydrolyzes GTP to GDP + Pi. (GTPase).

The presence of GDP on Ga causes it to rebind to the inhibitory bgcomplex.

Adenylate Cyclase is no longer activated.

2. Phosphodiesterases catalyze hydrolysis of cAMP AMP.

Turn off of the signal:

DAG & IP3

Phosphotidylinositol Signal Transduction Pathway Protein kinase C activated by DAG and

calcium Synthesis of DAG and IP3

cGMPThe cGMP Signal Transduction Pathway

cGMP effects: lowering of blood pressure & decreasing

CHD risk Relaxation of cardiac muscle Vasodilation of vascular smooth muscle Increased excretion of sodium and water by

kidney Decreased aggregation by platelet cells

cGMPThe cGMP Signal Transduction Pathway

Two forms of guanylate cyclase

Membrane-bound Activated by ANF (atrial natriuretic factor)

ANF released when BP elevated

Cytosolic Activated by nitric oxide NO produced from arginine by NO synthase

Nitroglycerine slowly produces NO, relaxes cardiac and vascular smooth muscle, reduces angina

cAMP activates Protein Kinase G Phosphorylates smooth muscle proteins

cGMPThe cGMP Signal Transduction Pathway