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

Parathyroid hormone (PTH) – the definition A protein hormone from the Parathyroid gland that regulates the metabolism of : Calcium and phosphorus ions in the body It is also called as Parathormone (PTH)

Parathyroid Glands – the source of Parathormone

Parathormone (PTH) – the background ↑ Ca and↓PO4 ions Parathormone is a protein hormone secreted by the Chief cells of the Parathyroid gland – 84 AAs It is one of the major hormones regulating the serum and extracellular concentration of : Calcium and Phosphate Ions and 1 Activation of Vitamin D in kidneys 2

PTH – the target organs - 3 Bone, kidney and Intestine 10/23/2017 PTH – the target organs - 3 Bone, kidney and Intestine Target organs are the ones with PTH receptors and include bones, Kidneys and Intestine These are Osteocytes, Osteoblasts and Renal tubules No receptors for Intestinal mucosa and Osteoclasts PTH acts via Osteoblasts, Osteocytes and activated Vitamin D in Kidney to ↑Ca++ absorption from GIT

Biosynthesis of PTH – As Pre Prohormone from RER to Golgi 10/23/2017 Biosynthesis of PTH – As Pre Prohormone from RER to Golgi PTH is synthesized as a Pre Prohormone in the RER of the Chief cells with115 AAs Pre-Pro PTH is cleaved by signal peptidase to remove 25 AAs and is converted to Pro- PTH Pro – PTH - 115 - 25 = 90 amino acids

Pro - PTH is transferred to Golgi 6 AAs are removed 10/23/2017 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 and 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 and ECF

Biosynthesis of PTH

Regulation of PTH – 2 pathways 10/23/2017 Regulation of PTH – 2 pathways PTH is regulated through negative feed back mechanism Regulation is through 2 pathways Direct and Indirect pathway

Regulation of PTH – Direct pathway No role of Calcitonin It is the interaction between Ca++ level and PTH secretion Low serum calcium ions level is sensed by the Calcium sensory receptors of the Chief cells It ↑ the transcription of mRNA, release of PTH from the Chief cells that ↑ Ca++ level It is achieved by acting on target organs (bone and Kidneys) There is no role of Calcitonin

Regulation of PTH – Direct pathway

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 ↓Transcription of mRNA for PTH (synthesis) 1 Auto degradation of the preformed secretary granules that ↓ the release of PTH 2 Release of Calcitonin to ↓ the Calcium by  its renal 3 excretion and bone resorption `

Homeostasis of blood calcium Role of Calcitonin and PTH

PTH - Mechanism of Action Activation of GPCR – PTHR1 PTH is a peptide hormone and its action is like the similar ones PTH binds to the Extracellular domain of the PTHR1 on the membranes of bones and kidneys. This binding produces conformal changes in the receptor It activates the intracellular α - subunit of the G protein to produce α – GTP in exchange for α- GDP

PTH - Mechanism of action ( PTHR1) activation of adnylate cyclase 10/23/2017 PTH - Mechanism of action ( PTHR1) activation of adnylate cyclase α- GTP activates the membranous Adenylate Cyclase of the target cells that Acts on the Cytoplasmic ATP : to form c AMP – the 2nd messenger C AMP activates the Protein kinas A, that Phosphorylates the specific intracellular enzymes/ proteins to execute the hormonal effects - ↑in serum Ca++

Mechanism of Action of PTH – PTHR1

PTH – Alternate mechanism activation of Phospholipase C An alternate mechanism of action is that : Activated G- Protein also stimulates the membranous Phospholipase C that converts the : Membranous Phospholipid PIP2 into IP3 and DAG as 2nd messengers that act on the bone, kidneys and intestine : To ↑ serum and extracellular Ca++

PTH mechanism of action – Dual pathways

Metabolic actions of PTH PTH acts to maintain the serum level of Ca++ B/ W 9.5- 11mg/dl and Po4 B/W 3 - 4.5 mg/dl As well as extracellular Ca++ and Po4 ions PTH has metabolic actions on : Bones, Kidneys and Intestine

Metabolic role of PTH – the target organs

PTH - Metabolic actions on bone 10/23/2017 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 membranous Ca++ pump and elevated Phosphatases around osteoclasts Membranous Ca++ pump is activated by PTH

Activated Osteoclasts

PTH and bone – Role of membranous Ca++ pump Osteoclasts has no PTH receptors Act through Osteoblasts and Osteocytes with PTH R1 and membranous calcium pump Membranous calcium pump in these bone cells is activated by PTH

Membranous Calcium pump – How it works 10/23/2017 Membranous Calcium pump – How it works Calcium pump causes rapid removal of calcium phosphates from the sites near these cells Calcium phosphate salts are transported to the extra cellular fluid by : altering the permeability of Osteocytes to calcium

Metabolic action on Kidneys ↑ Cal. Resorption and Po4 e xcretion PTH ↑ the renal excretion of Phosphates to decrease its plasma concentration and 1 Enhances the 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

Metabolic actions on Kidneys cont. Activation of Vit.D for GIT PTH ↑ the activation of Vitamin D to 1-25 Dehydroxy Cholecalceferol in kidneys (1st hydroxylation in liver 2nd kidneys) Vita. D promotes calcium absorption from Intestinal mucosa Intestinal absorption is facilitated by Calbindin (Ca binding protein) No PTH receptors on Intestinal mucosa There is no significant effect on Po4 absorption by intestine

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

PTH excess - hyperparathyroidism Excess of PTH, increases bone resorption or Osteolysis 2 types of hyperparathyroidism: Primary and secondary, resulting in: Osteoporosis, pathological fractures and : Defective bone formation including Cysts formation

PTH deficiency – Hypo para - thyroidism It is the low level of PTH in blood, caused by inborn metabolism and autoimmune disorders Hypo parathyroidism results in : Reduction of Serum calcium Defects in muscle contraction Tetany

Parathormone Calcitonin Site of synthesis RER of chief cell of parathyroid gland – A protein hormone RER of Para follicular cells of thyroid gland – A protein hormone Structure A Prohormone with 115 AAs – processed in Golgi to 84 AAs A Prohormone with 115 / 142 as processed in Golgi to 32 AAs. Target organs 3 – bone, kidney and intestinal mucosa no receptors for Osteoclasts and intestinal mucosa 2 – bones and renal tubular cells – no receptors at Osteoclasts, but present at other bone cells and kidneys Nature of Action Increases the calcium from Low to High via osteoclastic activity Decreases serum Ca level when high Via osteoblastic activity and inhibiting PTH Regulation of secretion Direct – interaction B/W low calcium and parathyroid gland Indirect – interaction B/W high calcium PTH and Calcitonin Direct – interaction B/W high serum and ECF and Calcitonin Indirect – interaction B/W low Ca level and Calcitonin and PTH Stimulates PTH secretion to increase Ca level in serum and ECF Metabolic Actions Via 2nd messenger (cAMP) Maintains the serum concentration of Ca B/W 9.5 – 10.5mg /dl and PO 3.5 – 4.5 mg/dl Maintains the Ca level in serum and ECF by reducing the Osteoclastic activity when high Secretion Abnormalities Excess – hyperparathyroidism osteoporosis, pathological fracture Deficiency low Ca level tetany and defects in muscle contraction Not significant Excess or Deficiency – used in the treatment of post menopausal osteoporosis and malignancies