3 rd lecture: mechanism of hormones action hormones acting through intracellular receptors: ...

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Page 1: 3 rd lecture: Mechanism of hormones action  Hormones Acting Through Intracellular Receptors:  Hormones Acting Through Plasma Membrane Receptors.  Structure
Page 2: 3 rd lecture: Mechanism of hormones action  Hormones Acting Through Intracellular Receptors:  Hormones Acting Through Plasma Membrane Receptors.  Structure

3rd lecture:Mechanism of hormones actionHormones Acting Through Intracellular Receptors:Hormones Acting Through Plasma Membrane

Receptors.Structure of plasma membrane receptor Intracellular 2nd MessengersG-Protein Coupled Receptors:Enzyme Linked Receptor.

Hormonal regulation of tissue metabolism:

Insulinglucagon

Page 3: 3 rd lecture: Mechanism of hormones action  Hormones Acting Through Intracellular Receptors:  Hormones Acting Through Plasma Membrane Receptors.  Structure

B) Hormones acting through Plasma Membrane Receptors:

The most important plasma membrane receptors are:

1- G-protein - linked Receptors 2- Tyrosine Kinase - linked

Receptors.

Page 4: 3 rd lecture: Mechanism of hormones action  Hormones Acting Through Intracellular Receptors:  Hormones Acting Through Plasma Membrane Receptors.  Structure

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: GTP ase

GTP + H2O GDP + Pi

1]- Hormones Acting Through G-protein-linked Membrane Receptors (group II hormones)

Page 5: 3 rd lecture: Mechanism of hormones action  Hormones Acting Through Intracellular Receptors:  Hormones Acting Through Plasma Membrane Receptors.  Structure

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

Page 6: 3 rd lecture: Mechanism of hormones action  Hormones Acting Through Intracellular Receptors:  Hormones Acting Through Plasma Membrane Receptors.  Structure

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.

intracellular,

extracellular,

membrane

Page 7: 3 rd lecture: Mechanism of hormones action  Hormones Acting Through Intracellular Receptors:  Hormones Acting Through Plasma Membrane Receptors.  Structure

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 -subunit diffuses along the plasma membrane and binds to the effector enzyme (AC) lead to activation of this effector enzyme (adenylate cyclase)

Page 8: 3 rd lecture: Mechanism of hormones action  Hormones Acting Through Intracellular Receptors:  Hormones Acting Through Plasma Membrane Receptors.  Structure

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

GTP aseGTP + H2O GDP + Pi

Page 9: 3 rd lecture: Mechanism of hormones action  Hormones Acting Through Intracellular Receptors:  Hormones Acting Through Plasma Membrane Receptors.  Structure

Hormones Acting Through G-protein-linked Membrane

Receptors

AC

hormone signal outside GPCR plasma membrane

GTP GDP ATP cAMP + PP i

cytosol

GDP GTP

Page 10: 3 rd lecture: Mechanism of hormones action  Hormones Acting Through Intracellular Receptors:  Hormones Acting Through Plasma Membrane Receptors.  Structure

A- Possessing intrinsic tyrosine kinase activity.

e.g. Insulin.B- Associated with a protein that is

tyrosine kinase enzyme.

e.g. Growth hormone

2]- Hormones acting through Tyrosine Kinase - linked receptors:

Page 11: 3 rd lecture: Mechanism of hormones action  Hormones Acting Through Intracellular Receptors:  Hormones Acting Through Plasma Membrane Receptors.  Structure

A- Possessing intrinsic tyrosine kinase activity:

e.g. Insulin1- Binding of hormone to its specific receptor

stimulates the auto-phosphorylation of the tyrosine kinase residue of the receptor its activation

Page 12: 3 rd lecture: Mechanism of hormones action  Hormones Acting Through Intracellular Receptors:  Hormones Acting Through Plasma Membrane Receptors.  Structure

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.

Page 13: 3 rd lecture: Mechanism of hormones action  Hormones Acting Through Intracellular Receptors:  Hormones Acting Through Plasma Membrane Receptors.  Structure
Page 14: 3 rd lecture: Mechanism of hormones action  Hormones Acting Through Intracellular Receptors:  Hormones Acting Through Plasma Membrane Receptors.  Structure

[1] Insulin

It is produced by cell of pancreas.

It is polypeptide consisting of two chains A and B, linked by disulfide bridges.

Page 15: 3 rd lecture: Mechanism of hormones action  Hormones Acting Through Intracellular Receptors:  Hormones Acting Through Plasma Membrane Receptors.  Structure

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.

Page 16: 3 rd lecture: Mechanism of hormones action  Hormones Acting Through Intracellular Receptors:  Hormones Acting Through Plasma Membrane Receptors.  Structure

Catabolism of insulin - Mainly occurred in liver and kidney.

Two enzyme systems are involved:

1) An insulin-specific protease2) Glutathione-insulin trans-hydrogenase

(insulinase) which is more important and responsible for reductive cleavage of "S-S bond".

Page 17: 3 rd lecture: Mechanism of hormones action  Hormones Acting Through Intracellular Receptors:  Hormones Acting Through Plasma Membrane Receptors.  Structure

Insulin receptor

Page 18: 3 rd lecture: Mechanism of hormones action  Hormones Acting Through Intracellular Receptors:  Hormones Acting Through Plasma Membrane Receptors.  Structure

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- glycolysis4- TCA Cycle 5- glycogenesis in liver and muscle.6- Decreasing gluconeogenesis 8- glycogenolysis

Page 19: 3 rd lecture: Mechanism of hormones action  Hormones Acting Through Intracellular Receptors:  Hormones Acting Through Plasma Membrane Receptors.  Structure

2) Lipid metabolism: Lipogenic effect:1- Decreasing lipolysis2- 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.

Page 20: 3 rd lecture: Mechanism of hormones action  Hormones Acting Through Intracellular Receptors:  Hormones Acting Through Plasma Membrane Receptors.  Structure

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).

Page 21: 3 rd lecture: Mechanism of hormones action  Hormones Acting Through Intracellular Receptors:  Hormones Acting Through Plasma Membrane Receptors.  Structure

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

Page 22: 3 rd lecture: Mechanism of hormones action  Hormones Acting Through Intracellular Receptors:  Hormones Acting Through Plasma Membrane Receptors.  Structure

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:

Page 23: 3 rd lecture: Mechanism of hormones action  Hormones Acting Through Intracellular Receptors:  Hormones Acting Through Plasma Membrane Receptors.  Structure

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

Page 24: 3 rd lecture: Mechanism of hormones action  Hormones Acting Through Intracellular Receptors:  Hormones Acting Through Plasma Membrane Receptors.  Structure
Page 25: 3 rd lecture: Mechanism of hormones action  Hormones Acting Through Intracellular Receptors:  Hormones Acting Through Plasma Membrane Receptors.  Structure