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Parathyroid hormone(Parathormone) Lecture NO: 2 nd MBBS

Parathyroid hormone(Parathormone) Lecture NO: 2 nd MBBS. Dr Muhammad Ramzan. Parathyroid hormone (PTH) – the definition. A protein hormone (84 AA.) from the Parathyroid gland that regulates the metabolism of : Calcium and phosphorous in the body It is also called as Parathormone (PTH)

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Parathyroid hormone(Parathormone) Lecture NO: 2 nd MBBS

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  1. Parathyroid hormone(Parathormone) Lecture NO: 2nd MBBS Dr Muhammad Ramzan

  2. Parathyroid hormone (PTH) – the definition • A protein hormone (84 AA.) from the Parathyroid gland that regulates the metabolism of : • Calcium and phosphorous in the body • It is also called as Parathormone (PTH) • www.merrium – webster.com

  3. Parathormone (PTH) – the background↑ Ca and↓PO4 ions • PTH is important in bone remodeling via ongoing process of bone resorption and bone formation (Osteogenesis) • PTH elevates calcium level when it is low. • PTH excess causes bone/muscle pain and kidney stones • PTH deficiency produces muscle spasm; numbness in extremities, coagulation disorders and abnormal heart beats • www.webmd.com – www.wikipedia.com

  4. PTH – the target organs - 3 Bone, kidney and Intestine • Target organs are the ones with PTH receptors and include bones, Kidneys (CNS) and Intestine • No receptors for Intestinal mucosa and Osteoclasts • PTH acts via Osteoblasts and Osteocytes • Activates Vit. D in Kidneys through 1- α – hydroxylase to • Increase GIT Ca++ absorption • www. Labtestsonline.org

  5. Target organs of PTH

  6. Biosynthesis of PTH – As Pre Prohormone • PTH is synthesized as a Pre Prohormone in the RER of the Chief cells with115 AAs • Pre-Pro PTH is cleaved by signal peptidase in RER to remove 25 AAs and is converted to Pro- PTH • Pro – PTH - 115 - 25 = 90 amino acids

  7. Pro - PTH is transferred to Golgi 6 AAs are removed • Pro - PTH is transferred to the Golgi Complex and 6 AAs are removed by Clipase for PTH = 84 AAs • PTH is packed/stored as secretary vesicles in Chief cells • Hormone Is released to the circulation in response to a proper physiological stimulus like: • Low Ca++ level in serum/ ECF

  8. Biosynthesis of PTH

  9. Regulation of PTH – 2 pathways • PTH is regulated through negative feed back mechanism • Regulation is through 2 pathways • Direct and • Indirect

  10. Regulation of PTH – Direct pathwayNo role of Calcitonin • It is the interaction B/W Ca++level and PTH secretion • Lowfreecalcium (Ions) in ECF is sensed by the Calcium sensory receptors - Integral membrane proteins • It ↑ the secretion of PTH that elevates Ca++ level by its action on the target organs (bones and Kidneys) • There is no role of Calcitonin • www.vivo. colostate.com

  11. Regulation of PTH – Direct pathway

  12. PTH Regulation – Indirect pathway ↑ Ca, PTH and Calcitonin • It is interaction B/w high serum Ca++, PTH and Calcitonin • High serum Ca++ Induces the following changes • 1. ↓Transcription of mRNA for PTH (synthesis) • 2. Auto degradation of the preformed PTH secretary granules • Secretion of Calcitonin reduces the Ca++ by promoting its renal excretion and bone formation

  13. Homeostasis of blood calciumRole of Calcitonin and PTH

  14. PTH - Mechanism of ActionActivation of GPCR – PTHR1 • PTH is a protein hormone and its action is like the similar ones • PTH binds to the Extracellular domain of the PTHR1 on the membranes of bones to produce some changes • It activates the intracellular α - subunit of the G protein to produce α – GTP in exchange for α- GDP

  15. PTH - Mechanism of action ( PTHR1) activation of adnylate cyclase • α- GTP activates the membranous Adenylate Cyclase of the target cells that convert ATP to cAMP • cAMP is the 2nd messenger • cAMP activates the Protein kinas A, that Phosphorylates the specific intracellular enzymes/ proteins • to execute the hormonal effects - ↑ serum Calcium

  16. Mechanism of Action of PTH – PTHR1

  17. PTH – Alternate mechanismactivation of Phospholipase C • An alternate mechanism of action of PTH • Activated α GTP also stimulates Phospholipase C • It converts membranous Phospholipid, PIP2 into: • IP3 and DAG as 2nd messengers • Both act on the bone, kidneys and intestine to increase extracellular Calcium

  18. PTH mechanism of action – Dual pathways

  19. Metabolic actions of PTH • PTH acts to maintain serum/ECF Calcium between • 9.5 - 11mg/dl and Po4B/W 3 - 4.5 mg/dl • PTH has significant metabolic actions on : • Bones, Kidneys and Intestine

  20. Metabolic role of PTH – the target organs

  21. PTH - Metabolic actions on bone • Bone is a large reservoir of Calcium • PTH enhances the release of Ca and Po4 from the bone by Osteolysis via Osteoclasts - a normal process • Osteolysis is also supported by the : • 1. Membranous Calcium pumpactivated by PTH • 2. Elevated Phosphatases around Osteoclasts

  22. Activated Osteoclasts

  23. Membranous Calcium pump – How it works • Calcium pump causes rapid removal of calcium phosphate from the sites near these cells (Osteoclasts) • Calcium phosphate salts are transported to ECF as: • It alters the permeability of Osteocytes to calcium

  24. Metabolic action on Kidneys↑ Cal. Resorption and Po4 excretion • PTH promotes renalexcretion of Phosphates to decrease its plasma level and 1 • Enhances active resorption of Ca and Mg from the distal tubules and ascending loop of Henley 2 • This increases Calcium phosphate ratio (3:11) and more free Ca++ ions in circulation

  25. Metabolic actions on Kidneys cont.Activation of Vit.D for GIT • PTH promote activation of Vitamin D to 1-25 Dihydroxy Cholecalceferol in kidneys via 1- α- hydroxylase • Vita. D promotes calcium absorption from GIT • It is facilitated by Calbindin (Ca binding protein) • No PTH receptors are present on Intestinal mucosa • PTH has no significant effect on Po4 absorption by GIT

  26. PTH - secretion abnormalities • Parathormone may be secreted in excess or there may be deficiency of PTH secretion • Both abnormalities lead to significant clinical conditions

  27. PTH excess - hyperparathyroidism • Excessive PTH secretion is classified as : • Primary and secondary • Primary one is the result of diseases of parathyroid and is due to tumour of the gland • Results in hypercalcemia, kidney stones and osteoporosis

  28. Hyperparathyroidism - Secondary • Secondary one is due to causes out side the parathyroid • Common cause is the: • 1. Renal disease/ failure as it is unable to reabsorb Calcium and there is fall in blood Ca. • 2. Malnutrition for Calcium and Vit. D produces : • Decalcification of bone leading to rubber bones, • pathological fractures and cyst formation

  29. PTH deficiency – Hyoparathyroidism • It refers to the condition when PTH is produced less than the body requirements. Caused by: • Inborn error of metabolism and autoimmune disorders. • Hyoparathyroidism results in : • 1. Reduction of Serum calcium • 2. Defects in muscle contraction and • 3. Tetany

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