1. Cell Signaling And Hormonal Regulation

2. 3rd lecture: Mechanism of hormones action
Hormones Acting Through Intracellular Receptors:
Hormones Acting Through Plasma Membrane Receptors.
Structure of plasma membrane receptor
Intracellular 2nd Messengers
G-Protein Coupled Receptors:
Enzyme Linked Receptor.
Hormonal regulation of tissue metabolism:
Insulin
glucagon

3. B) Hormones acting through Plasma Membrane Receptors:
The most important plasma membrane receptors are:
1- G-protein - linked Receptors
2- Tyrosine Kinase - linked Receptors.

4. 1]- Hormones Acting Through G-protein-linked Membrane Receptors (group II hormones)
Structure of G-proteins:
1- G-proteins (guanine nucleotide-binding proteins)-have a common three subunits:
G, G and G subunites.
2- Each G-protein has a unique -subunit.
3- This unique -subunit has the capacity to bind GDP or GTP
4- then, this unique -subunit catalyses the following reversible reaction:

5. Structure of G-proteins-liked Plasma Membrane receptore: 1- Plasma Membrane receptor G-protein 3- effector enzyme -Specific Plasma Membrane G protein-coupled receptors (GPCRs) - Effector enzyme, must be present for the action of the hormone

6. Mechanism of action :
1- On binding of hormone with G protein-coupled receptors (GPCRs) conformational change of the receptor takes place activation of G-protein complex.
extracellular,
membrane
intracellular,

7. 2- This activation results in conversion of GDP
linked to the -subunit to GTP.
3- GTP-linked  -subunit dissociates from - subunits.
4- The GTP-linked a-subunit diffuses along the plasma membrane and binds to the effector enzyme (AC) lead to activation of this effector enzyme (adenylate cyclase)

8. 5- Activation of effector enzyme generation of a specific Second Messenger (cAMP ; Phosphatidyl Inositols and Ca2+) 6- Activation of the effector enzyme is ceased when the GTPase activity of G-protein hydrolyses: GDP -subunit then diffuses back, along the membrane, and re-associates with -subunits. 8- the second messenger generated can mediates the different actions of the hormone

9. Hormones Acting Through G-protein-linked Membrane Receptors

10. e.g. Insulin. e.g. Growth hormone
2]- Hormones acting through Tyrosine Kinase - linked receptors:
A- Possessing intrinsic tyrosine kinase activity.
e.g. Insulin.
B- Associated with a protein that is tyrosine kinase enzyme.
e.g. Growth hormone

11. A- Possessing intrinsic tyrosine kinase activity:
e.g. Insulin
1- Binding of hormone to its specific receptor stimulates the auto-phosphorylation of the tyrosine kinase residue of the receptor its activation

12. 2- The active tyrosine kinase residue of the receptor transfers the terminal phosphate from ATP to the hydroxyl group of tyrosine residue of selected proteins (enzyme or other cellular protein)
3- The phospho-tyrosyl protein may be the active or the inactive form of the selected enzyme
regulation of specific physiologic function in the target cell.

13. Hormonal Regulation Of Tissue Metabolism: Insulin glucagon

14. [1] Insulin It is produced by b-cell of pancreas.
It is polypeptide consisting of two chains A and B, linked by disulfide bridges.

15. Biosynthesis of Insulin:
1- Insulin is formed as pre-pro-insulin 2- then, converted to pro-insulin 3-finally to insulin + c-peptide Insulin stored in secretory granules in the B-cell.

16. Catabolism of insulin Two enzyme systems are involved:
Mainly occurred in liver and kidney.
Two enzyme systems are involved:
1) An insulin-specific protease
2) Glutathione-insulin trans-hydrogenase (insulinase) which is more important and responsible for reductive cleavage of "S-S bond".

17. Insulin receptor

18. Metabolic Roles of Insulin:
1) On Carbohydrate Metabolism:
Insulin blood glucose
glycogen store.
These effects are mediated by:
1- glucose uptake by various tissues.
glycolysis
TCA Cycle
5- glycogenesis in liver and muscle.
6- Decreasing gluconeogenesis
glycogenolysis

19. 2) Lipid metabolism: Lipogenic effect: 1- Decreasing lipolysis
2- Increasing FA synthesis via:
3- Increasing TG synthesis in adipose tissue,
3) Protein metabolism: anabolic, via:
1- Increases amino acid uptake.
2- Insulin is necessary for the protein anabolic effect of GH (permissive effect).
3- Insulin affects gene transcription by regulating specific mRNA synthesis.

20. 4) Action on mineral metabolism:
Insulin causes lowering in the concentration of K+ and Pi in blood via enhancing: glucose phosphorylation; protein kinases(all required Pi).

21. [2] Glucagon
It is produced by -cell of pancreas. It is single polypeptide, synthesized as pro-hormone which undergoes proteolytic cleavage to active hormone.

22. Metabolic Role of glucagon:
Actions of glucagon oppose those of insulin.
1) Effect on Carbohydrate metabolism:
Clucagon increases blood glucose via:
1- Increased hepatic glycogenolysis (not muscle glycogenolysis as muscle lacks glucagon receptors).
2- Increased hepatic gluconeogenesis by:

23. 2) Effect on Lipid Metabolism:
1- Increased lipolysis in adipose tissue
increased TG breakdown ↑ plasma FFA and glycerol.
2- Reduces FA synthesis (Antilipogenic action).
3) Effect on Protein Metabolism:
1- inhibits protein synthesis
2- Stimulate of hepatic protein catabolism.
4) Calorigenic action:
increases heat production and basal metabolic rate