1. 6/23/2016PARATHYROID HORMONE1 Parathyroid Hormone

2. 6/23/2016PARATHYROID HORMONE2 Parathyroid Hormone Important in calcium metabolism as well as in phosphate metabolism

3. 6/23/2016PARATHYROID HORMONE3 Anatomy of Parathyroid Glands Four parathyroid glands in the human being Develop at 5 – 14 weeks of gestation from 3 rd and 4 th branchial pouches They descend to lie posterior to the thyroid gland, One behind each of the upper and each of the lower poles of the thyroid Ectopic locations in the neck and mediastinum occur

4. 6/23/2016PARATHYROID HORMONE4 Anatomy of Parathyroid Glands Total wt of adult parathyroid tissue is about 130mg, One gland with 30 – 50mg Their blood supply is from thyroid arteries

5. 6/23/2016PARATHYROID HORMONE5 Anatomy of Parathyroid Glands Histological appearance of the gland changes with age: The predominant cells (chief cells) Are present throughout life Source of PTH They have abundant glycogen, Golgi apparatus and few clusters of secretory granules

6. 6/23/2016PARATHYROID HORMONE6 Anatomy of Parathyroid Glands Oxyphil cell First appears at puberty Distinguished by an eosinophilic cytoplasm Believed to be modified or depleted chief cells that no longer secrete hormone

7. 6/23/2016PARATHYROID HORMONE7 Synthesis and Release of PTH Synthesized on the ribosomes in the form of a preprohormone,(prepro- PTH) A polypeptide chain of 115AA Prepro-PTH is transported to ER Where it is cleaved to a prohormone with 90AA A leader sequence containing 25AA residues is removed from the n-terminal

8. 6/23/2016PARATHYROID HORMONE8 H2N-Met-Met-Ser-----------------------Gly-Lys---- Gln-Ser------Phe-Asn--------Val-Ser-Arg---- ----------- Leader sequence C-fragment sequence Active sequence Pro-sequence Prepro-PTH

9. 6/23/2016PARATHYROID HORMONE9 Gln-Ser------Phe-Asn--------Val-Ser-Arg---- ----------- C-fragment sequence Active sequence Pro-sequence H2N-Lys------ Pro-PTH

10. 6/23/2016PARATHYROID HORMONE10 Synthesis and Release of PTH Pro-PTH is transported to Golgi apparatus Additional 6AA residues are removed From the n-terminal to form PTH with 84aa,mw 9500

11. 6/23/2016PARATHYROID HORMONE11 Gln-Ser------Phe-Asn-------Val-Ser-Arg---- ----------- C-fragment sequence Active sequence Pro-sequence H2N-Lys-----

12. 6/23/2016PARATHYROID HORMONE12 Gln-Ser------Phe-Asn------------Val-Ser-NH 2 C-fragment sequence Active sequence Parathyroid hormone 1 84

13. 6/23/2016PARATHYROID HORMONE13 Synthesis and Release of PTH Finally packaged in secretory granules in the cytoplasm of cells Plasma level of intact PTH is 10-55 pg/ml Half life of less than 20min

14. 6/23/2016PARATHYROID HORMONE14 Synthesis and Release of PTH Biological activity resides in the n- terminal portion of the molecule within amino acid 1 – 27 The first 2AA are essential Cleavage of PTH between AA 33, and 40 also occur Leading to smaller compounds with as few as 34AA adjacent to the N- terminus of the molecule

15. 6/23/2016PARATHYROID HORMONE15 PTH Actions Its paramount effect is to increase plasma Ca2+ levels by Stimulating bone resorption Renal tubular Ca2+ reabsorption And 1,25 – (OH) 2 D 3 synthesis PTH decrease plasma phosphate concentration By Inhibiting renal tubular phosphate reabsorption

16. 6/23/2016PARATHYROID HORMONE16 Mechanism of PTH Actions PTH action is initiated by binding to a plasma cell membrane receptor This is glyprotein composed of multiple subunits of 85,000mw The 14 to 34 regions of PTH contains the binding sequence

17. 6/23/2016PARATHYROID HORMONE17 Mechanism of PTH Actions Interaction of PTH with receptors on the surface of target cells ↑ The formation of camp and of IP 3 and DAG

18. 6/23/2016PARATHYROID HORMONE18 Mechanism of PTH Actions The PTH receptor is coupled to adenyl cyclase through stimulatory G proteins (Gs) And to phospholipase C through another G protein Consequently, protein kinase A and C are activated and intracellular calcium is increased

19. 6/23/2016PARATHYROID HORMONE19 PLC Phospholipids Plasma membrane PTH Phosphatidy linositol IP 3 DAG Arachidonic acid PG’s Protein kinase C activity Ca 2+ Enzyme activities Metabolic pathways ER or Modulate cell response Gs protein

20. 6/23/2016PARATHYROID HORMONE20 ATP cAMP Prot kinase A Eg Protein synthesis Phosphorylated prot. Adenyl cyclae G- Prot Gs/GI PTH Biological effect

21. 6/23/2016PARATHYROID HORMONE21 Mechanism of PTH Actions Rapid responses almost certainly result from protein phosphorylation whereas delayed responses result from altered expression of genes

22. 6/23/2016PARATHYROID HORMONE22 Effects of PTH: The overall effect of PTH is To increase plasma calcium and decrease plasma phosphate By acting on 3 major target organs Bone Kidney GIT

23. 6/23/2016PARATHYROID HORMONE23 Calcium and Phosphate Absorption From the Bone PTH accelerates removal of calcium and phosphate from bone By 2 phases Rapid phase Slow phase

24. 6/23/2016PARATHYROID HORMONE24 Rapid Phase of Calcium and Phosphate Absorption PTH stimulates osteolysis Begins in minutes and increases progressively for several hours Note: bone fluid&osteocytic membrane

25. 6/23/2016PARATHYROID HORMONE25 Rapid Phase of Calcium and Phosphate Absorption PTH stimulates osteolysis By increaseing calcium permeability of the osteocytic membrane osteolysis occurs without absorption of bone’s fibrous and gel matrix

26. 6/23/2016PARATHYROID HORMONE26 Slow Phase of Calcium and Phosphate Absorption PTH activates the osteoclasts Requires several days or even weeks to become fully developed It also stimulates the formation of new osteoclasts Osteoclasts reabsorb bone itself Not merely reabsorption of calcium phosphate salt from the bone

27. 6/23/2016PARATHYROID HORMONE27 Slow Phase of Calcium and Phosphate Absorption Osteoclasts do not have membrane receptor proteins for PTH

28. 6/23/2016PARATHYROID HORMONE28 Slow Phase of Calcium and Phosphate Absorption It is believed that activated osteoblasts and osteocytes Send a secondary but unknown signal to the osteoclasts Causing them to set their usual task of bone reabsorption

29. 6/23/2016PARATHYROID HORMONE29 Slow Phase of Calcium and Phosphate Absorption After few months, osteoclastic resorption of bone can lead to weakened bones and secondary stimulation of the osteoblasts that attempt to correct the weakened state

30. 6/23/2016PARATHYROID HORMONE30 Slow Phase of Calcium and Phosphate Absorption PTH also induces increase in acid Phosphatase and carbonic ahydrase and accumulates of lactic acid and citric acid The resultant lowering of ph contributes to the resorptive process PTH also inhibits the synthesis of collagen by osteoblasts

31. 6/23/2016PARATHYROID HORMONE31 Effect of PTH in Kidneys PTH increase the reabsorption of calcium from the late distal tubules, collecting tubules and early collecting ducts

32. 6/23/2016PARATHYROID HORMONE32 Effect of PTH in Kidneys This effect is mediated by PTH stimulation of camp production at the capillary surface of the renal tubular cell Absolute amount of calcium excreted in the urine is elevated in PTH excess states Despite an increase in fractional reabsorption in the tubules

33. 6/23/2016PARATHYROID HORMONE33 Effect of PTH in Kidneys PTH inhibits the reabsorption of phosphates in the proximal tubules PTH also inhibits the reabsorption of Na+, and HCO3- in the proximal tubules

34. 6/23/2016PARATHYROID HORMONE34 Effect of PTH in Kidneys PTH stimulate reabsorption of mg2+ by the renal tubules, also H+ A most important action of PTH in the kidney Is to stimulate the synthesis of 1,25-(OH) 2 - D 3 Without PTH either none or almost none of the 1,25(oh)2-d3is formed

35. 6/23/2016PARATHYROID HORMONE35 Effects of PTH in GIT PTH greatly enhances both calcium and phosphate absorption from the intestines By increasing the formation of 1,25(OH)2-D3 in the kidneys

36. 6/23/2016PARATHYROID HORMONE36 Effects of PTH in Other Tissues/organs Alteration in the function of CNS, CVS, Muscles Peripheral nerves and of Other endocrine glands Are seen in states of PTH excess or deficiency

37. 6/23/2016PARATHYROID HORMONE37 Regulation of PTH Secretion The dominant regulator of parathyroid gland activity is plasma calcium level The hormone and the ion form a negative feedback pair Secretion of PTH is inversely related to the plasma [Ca 2+ ] in a sigmoid fashion

38. 6/23/2016PARATHYROID HORMONE38 Regulation of PTH Secretion 100 0% 234567234567 PTH secretion (% maximum) Plasma ionized Ca 2+ (mg/dl)

39. 6/23/2016PARATHYROID HORMONE39 Regulation of PTH Secretion Its is actually the ionized fraction of plasma calcium that regulates PTH secretion Suppression of PTH secretion by calcium Presents a notable exception to the usual rule That calcium influx into endocrine cells stimulates hormonal secretion

40. 6/23/2016PARATHYROID HORMONE40 Regulation of PTH Secretion Mechanism There are plasma membrane protein receptors for ionized calcium that responds to changes in ECF [Ca 2+ ] A low ionized Ca 2+ signal is transduced via a stimulatory Gs protein to adenyl cyclase The consequent increase in cAMP stimulate exocytosis of PTH – containing secretory granules. Calcium also modulates PTH synthesis and degradation within the glands

41. 6/23/2016PARATHYROID HORMONE41 Regulation of PTH Secretion Exposure to a high [Ca 2+ ] for hours to days depresses the rate of PTH synthesis by decreasing gene transcription Exposure for days to weeks decreases proliferation of parathyroid cells Thus elevated calcium levels decrease PTH synthesis, store, and release as well as, ultimately parathyroid cell mass

42. 6/23/2016PARATHYROID HORMONE42 Regulation of PTH Secretion Hypocalcaemia increases PTH Synthesis, stores, and secretory rate And ultimately stimulates growth of the gland Despite the close physiological relation of phosphate to calcium, No direct effect of phosphate on the parathyroid gland

43. 6/23/2016PARATHYROID HORMONE43 Regulation of PTH Secretion However a rise in plasma phosphate does cause a fall in ionized calcium levels which in turn stimulates PTH secretion 1,25- (OH)2 D3 inhibits synthesis of PTH and decrease PTH secretion Phosphadiesterase inhibitors, epinephrine,dopamine and histamine All stimulate PTH secretion

44. 6/23/2016PARATHYROID HORMONE44 Regulation of PTH secretion  - adrenergic agonists and prostaglandins inhibit PTH secretion by decreasing cAMP levels Excess Aluminium is also inhibitory PTH is inherently pulsatile. In addition there is circadian rhythm with a nocturnal peak this rhythm is independent of plasma Calcium levels