GH RECEPTORS.pptx
- 1. Cellular and molecular mechanism of action of Growth hormone Presented by: Mohd. Ashhar Suhail Nomani M.Pharm 2nd Semester Department of Pharmacology Jamia Hamdard, New Delhi 1
- 2. Presentation Outline • Introduction • Regulation of secretion • Growth Hormone Receptors • Actions of GH • Pathological involvements • GH Inhibitors • References 2
- 3. GROWTH HORMONE • Growth hormone(GH) or Somatotropic hormone(STH) is secreted by acidophil cell of anterior pituitary gland. • It is a polypeptide with 191 amino acid residue. • Maintains lean body mass and bone mass in adults. • Important for postnatal growth and development to adult size. 3
- 4. VARIATIONS IN PLASMA LEVEL OF GH • Birth to early childhood= hormone level increases • Children have higher secretion than adult • Puberty= have peak level of GH • Senescences= reduction of GH 4
- 5. REGULATION • Hypothalamic control • Negative feedback • Other control mechanisms 5
- 6. HYPOTHALMIC CONTROL • Control by 2 hormones • Growth hormone releasing hormone (GHRH) • Growth hormone inhibiting hormone (GHIH) 6
- 7. GROWTH HORMONE RELEASING HORMONE(GHRH) • Polypeptide with 44 amino acids. • Produced by hypothalamic neurons, stimulates GH secretion by binding to specific GPCR on somatotrophs in the anterior pituitary. • The stimulated GHRH receptor couples to Gs to raise intra-cellular levels of cAMP and Ca2+, thereby stimulating GH synthesis and secretion. 7
- 8. FACTORS STIMULATING GHRH SECRETION • Hypoglycemia- through glucoreceptors in ventromedial nucleus of hypothalamus(NE) • Emotions, exercise & physical stress- pain, surgery, trauma & inflammation. • Slow wave phase of sleep(5HT) • Certain amino acids- arginine after protein meal • Growth hormone releasing peptide(GHRP) – Ghrelin from oxyntic glands of stomach. 8
- 9. GROWTH HORMONE INHIBITING HORMONE(GHIH) • Somatostatin • Polypeptide with 14 amino acids • Factors stimulating GHIH- Hyperglycemia High FFA conc. 9
- 10. NEGATIVE FEEDBACK • By GH- by releasing somotostatin from hypothalamus • By GHRH- ultra short feedback loop • By Somotomedins- Insulin like growth factor (IGF) produced by action of growth hormone on target tissue. 10
- 11. OTHER CONTROL MECHANISMS • Throxine , cortisol • Insulin- represses GH gene expression • Placental growth hormone & lactogen • Obesity • Nuerotransmitters – DA, NE, Ach, 5HT, GABA, histamine • oestradiol 11
- 12. GROWTH HORMONE RECEPTORS • GH receptors of various sizes are present on the cell membrane in target tissues, including the liver and adipose tissue. • The GH receptor belongs to cytokine family of receptors and therefore follows JAK-STAT pathway of cellular mechanism. • It comprises a large extracellular portion, a transmembrane domain and a large intracellular cytoplasmic portion. 12
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- 14. Mechanism of Action • Binding of one GH molecule to extracellular domain of a GH- receptor diamer results in formation of ternary complex which undergoes a conformational change. • That is followed by dimerization of receptors and activation of tyrosine kinase enzyme known as Janus kinase 2 (Jak-2) • This Jak-2 phosphorylate each other and tyrosine residues of the receptor. • This leads to cascade of phosphorylation reactions result in activation of: - proteins transcription(STAT) - Mitogen activated protein(MAP) kinase - Phosphoinositide-3-kinase (PI kinase) • Overall results is linear growth and metabolism of carbohydrate, lipid, mineral & protein as well as regulation of gene expression. 14
- 15. ACTIONS OF GROWTH HORMONE • Growth promoting actions • Metabolic action • Lactogenic actions 15
- 16. GROWTH PROMOTING ACTIONS • Promotes linear growth. • Bone- stimulate osteoblastic activity converts cartilage into bone. • Increases bone mass. • Cartilage – stimulate proliferation of chondrocytes in epiphyseal end plate of long bones. 16
- 17. METABOLIC ACTION PROTEIN METABOLISM (Positive Nitrogen Balance) • Anabolic effect • Promotes protein deposition in tissue. • Increase amino acid uptake into cell • Increase protein synthesis by ribosomes. • Stimulates Transcription 17
- 18. FAT METABOLISM • Promotes Lipolysis in adipose tissue. • Increase fat utilization for energy. 18
- 19. CARBOHYDRATE METABOLISM • Antagonistic to insulin & produces hyperglycemia. • Increase Gluconeogenesis • Decrease uptake & utilization of glucose by by tissue for energy production • Inhibit Glycolysis • Increase Glycogen stores • Use FFA for energy production. 19
- 20. MINERAL METABOLISM • Promotes bone mineralization in growing children. • Through IGF1 causes positive balance for Ca, P and Mg. • Promotes reabsorption of Ca, P & Mg. 20
- 21. LACTOGENIC ACTIONS • Enhances milk production • Acts like Prolactin so called Prolactin like effect of growth hormone. 21
- 22. PATHOLOGICAL INVOLVEMENTS • Excess production of GH is responsible for gigantism in childhood and acromegaly in adults. • Hyposecretion of GH results in pituitary dwarfism. 22
- 23. GH INHIBITORS • Somatostatin – 14 amino acid long peptide, inhibits GH, PRL, TSH, insulin, glucagon, gastrin and HCl. • GI actions causes steatorrhoea (the excretion of abnormal quantities of fat with faeces), hypochlorhydria, dyspepsia and nausea. • Use in acromegaly is limited because of duration of action is short(2-3 min) • Octreotide- synthetic octapeptide surrogate of somatostatin • 40 times more potent in suppressing GH secretion • Longer acting( 90 min) therefore preferred over somatostatin for acromegaly. 23
- 24. • Lanreotide – long acting octapeptide SST analogue that causes prolonged suppression of GH secretion when administered subcutaneously. • Its efficacy appears comparable to that of octreotide. • Pegvisomant- GHR antagonist approved for treatment of acromegaly. • It binds to GHR but does not activate JAK-STAT signalling or stimulate IGF1 secretion. 24
- 25. REFERENCES • Mark E. Molitch and Bernard P. Schimmer, ‘The Hypothalamic – Pituitary Axis’; Goodman & Gilman’s ‘The Pharmacological Basis of Therapeutics’ 13th Edition 2017, pp. 771-778 • Ritter M. et al., 2020 Rang and Dale’s Pharmacology. 9th Ed., Edinburgh: Elsevier, pp 404-410 • F. Dehkhoda,Christine M.Lee, Andrew J. Brooks; 2018. ‘Growth Hormone Receptor’. Sec. Molecular and Structural Endocrinology 25