Parathyroid hormone - Stimulus, Physiological actions, Regulation I Calcium homeostasis 2 I Endocrine Physiology The slides will be about the following 1. Introduction 2. Stimulus of PTH secretion 3. Secretion of PTH 4. Mechanism of action of PTH 5. Physiological actions 6. Regulation of PTH secretion You can also watch the same topic on HM Learnings Youtube channel. You can also follow HM Learnings on facebook, instagram and twitter for daily updates

2. Parathyroid hormone (PTH)
• Peptide hormone
• Chief cells of parathyroid glands synthesizes and secretes parathyroid
hormone.
• 4 parathyroid glands, two located on the posterior surface of left lobe
and two more on the right.

3. Stimulus of PTH secretion
• major stimulus is low plasma ionized calcium level
• Other stimulus- low vitamin D levels, high plasma phosphate level

4. Secretion of PTH
• Calcium sensor receptor (GPCR) is located on plasma membrane of
chief cells. Ca2+ bind to these in a saturable manner.
• The affinity of these receptor depends on the concentration of calcium.
• When calcium binds, the CaSR activates Gq phospholipase C
• It lead to increase in DAG and IP3
• DAG activate PKC and IP3 bind to receptors on ER to release Ca2+ in
the cytoplasm.
• Increase in [Ca2+]i inhibit PTH secretion.
• Hypocalcemia also stimulates synthesis of PTH.

6. Mechanism of action of PTH
• PTH1R and PTH2R
• Kidney (PCT, DCT) and bone (preosteoblast, osteoblast) have the
greatest abundance of PTH1R.
• PTH1R is a GPCR
• PTH1R appears to be coupled to two heterotrimeric G proteins and
thus to two signal-transduction systems.
• Binding of PTH to the receptor stimulates Gαs , which in turn activates
adenylyl cyclase and thus releases cAMP and stimulates protein kinase A

7. • The activated PTH receptor also stimulates Gαq , which in turn
stimulates phospholipase C to generate IP3 and DAG. The IP3
releases Ca2+ from internal stores, thus increasing [Ca2+]i and activating
Ca2+ -dependent kinases
• PTH1R also binds PTH-related protein (PTHrP)

8. Physiological actions
• On Kidney- increase Ca2+ reabsorption in DCT, decrease phosphate
reabsorption resulting in phosphaturia.
• Phosphaturia results from a PTH-induced redistribution of Na/phosphate
cotransporters (NaPi-II) away from the apical membrane of the renal
proximal tubule and into a pool of subapical vesicles
• Vitamin D has a synergistic action to promote Ca2+ reabsorption in the DCT.
• PTH stimulates the hydroxylation of 25-hydroxy vitamin D3 by 1α renal
hydroxylase in the mitochondria of proximal tubule.
• PTH also induce the renal hydroxylation of 25-hydroxy vitamin by reducing
plasma FGF23.

9. Why PTH has opposite effect on Ca2+ &
PO4
2- in kidney?
• To maintain the solubility product.
• Solubility product = plasma calcium (in mg/dL) × plasma elemental
phosphorus (in mg/dL)
• If both plasma calcium and phosphate level rises, solubility product will
be increased and cause the formation of CaPO4 precipitates.

10. On bones- both bone resorption and bone
formation
• Bone Resorption by Indirect Stimulation of Osteoclasts
• The net effect of persistent increases of PTH on bone is to stimulate
bone resorption, thus increasing plasma [Ca 2+ ].
• Osteoblasts express abundant surface receptors for PTH; osteoclasts do
not.
• PTH acts on osteoblasts and osteoclast precursors to induce the
production of several cytokines that increase both the number and the
activity of bone-resorbing osteoclasts.
• PTH causes osteoblasts to release agents such as M-CSF and stimulates
the expression of RANKL, actions that promote the development of
osteoclasts from its precursors.

12. Bone deposition
• The intermittent increases in plasma [PTH] have predominately bone-
synthetic effects, inducing higher rates of bone formation and mineral
apposition.
• 3 mechanisms
1. PTH decreases the production of sclerostin by osteocytes. Lower
levels of plasma sclerostin promote osteoblastic differentiation and also
inhibit osteoblastic apoptosis.
2. PTH stimulates bone synthesis indirectly in that osteoclastic bone
resorption leads to the release of growth factors trapped within the
matrix; these include insulin-like growth factor 1 (IGF-1), IGF-2,
fibroblast growth factor 2 (FGF2), and transforming growth factor-β.
3. PTH stimulates osteoblasts to produce OPG and thereby interfere
with RANKL activation of osteoclasts

14. On intestine
• PTH increase renal hydroxylation of 25-hydroxy vitamin D
• This active form of vitamin D increase the absorption of Ca2+ from
intestine.

15. Regulation of PTH secretion
↓ Ca2+ serum level
Sensed by Ca sensing receptors (CaSR) on
parathyroid gland
Release of PTH
Acts on kidney,
intestine and bone
↑ in serum Ca2+ level

16. Regulation of PTH secretion

17. Regulation of PTH secretion
• The regulatory element for PTH gene also includes the response
elements for vitamin D and vitamin A
• Thus vitamin D VDR binding to its hormone response element will
decrease the rate of transcription of PTH

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