3 rd lecture: mechanism of hormones action hormones acting through intracellular receptors: ...
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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
B) Hormones acting through Plasma Membrane Receptors:
The most important plasma membrane receptors are:
1- G-protein - linked Receptors 2- Tyrosine Kinase - linked
Receptors.
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)
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.
intracellular,
extracellular,
membrane
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)
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
Hormones Acting Through G-protein-linked Membrane
Receptors
AC
hormone signal outside GPCR plasma membrane
GTP GDP ATP cAMP + PP i
cytosol
GDP GTP
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:
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
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.
[1] Insulin
It is produced by 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 - 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".
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- glycolysis4- TCA Cycle 5- glycogenesis in liver and muscle.6- Decreasing gluconeogenesis 8- glycogenolysis
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.
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] GlucagonIt 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