Cell Signaling And Hormonal Regulation

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

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

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:

Structure of G-proteins-liked Plasma Membrane receptore: 1- Plasma Membrane receptor. 2- G-protein 3- effector enzyme -Specific Plasma Membrane G protein-coupled receptors (GPCRs) - Effector enzyme, must be present for the action of the hormone

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,

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)

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: 7- 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

Hormones Acting Through G-protein-linked Membrane Receptors

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

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

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.

Hormonal Regulation Of Tissue Metabolism: Insulin glucagon

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

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.

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".

Insulin receptor

Metabolic Roles of Insulin: 1) On Carbohydrate Metabolism: Insulin blood glucose glycogen store. These effects are mediated by: 1- glucose uptake by various tissues. 2- glycolysis 4- TCA Cycle 5- glycogenesis in liver and muscle. 6- Decreasing gluconeogenesis 8- glycogenolysis

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.

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).

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

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:

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