1. Hormones, Receptors, and Communication Between Cells
MALIK ALQUB MD. PHD.

2. General principles

3. 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.

4. 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

5. Hormones, Receptors, and Communication Between Cells
Intracellular Receptors

6. 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

7. 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

8. Gated Channels
Voltage Gated
Ligand Gated

9. 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

10. Insulin Signal Transduction Cascades
Insulin 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

11. 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).

12. 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.

13. 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).

14. G-protein-linked receptors
Binding of hormone activates an enzyme via a G-protein communication link.
The enzymes produces intracellular messengers
cAMP
diacylglycerol (DAG))

15. Intracellular Messengers: Signal Transduction Pathways
Cyclic AMP (cAMP)
Diacylglycerol (DAG) & Inositol Triphosphate (IP3)
Cyclic GMP (cGMP)

16. G-Protein-Linked Receptors:
Two types of G-Proteins
Stimulating G protein (Gs)
Activate adenylate cyclase
Inhibitory G proteins (Gi)
Inhibit adenylate cyclase

17. G Proteins
G proteins are trimers
Three protein units
Alpha
Beta
gamma

18. 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

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

20. 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)

21. 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

22. Activation of Protein Kinase A by cAMP
Activates or inhibits several enzymes of CHO and Lipid metabolism
Inactive form: regulatory+catalytic subunits associated
Active form: binding of cAMP disassociates subunits

23. Turn off of the signal: 1. Ga hydrolyzes GTP to GDP + Pi. (GTPase).
The presence of GDP on Ga causes it to rebind to the inhibitory bg complex.
Adenylate Cyclase is no longer activated.
2. Phosphodiesterases catalyze hydrolysis of
cAMP  AMP.

24. DAG & IP3 Phosphotidylinositol Signal Transduction Pathway
Protein kinase C activated by DAG and calcium
Synthesis of DAG and IP3

25. cGMP The 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

26. cGMP The 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

27. cGMP The cGMP Signal Transduction Pathway