2H Calcium & Phosphate review

What type of hormone is parathyroid hormone? Where is it produced?

84 AA polypeptide produced by principle cells (found inside or outside of thyroid

What type of hormone is calcitonin? How and where is it synthesized?

32 AA poly peptide produced via transcription/translation by thyroid parafollicular cells

What type of hormone is calcitriol? How is it synthesized?

Secosteroid synthesized via enzymatic modification of 7-dehydrocholesterol or vitamin D3

How and where is 7-dehydrocholesterol converted to cholecalciferol (Vitamin D3)?

UV light opens B ring of cholesterol in the skin.

How can vitamin D3 be obtained?

Via diet UV light

How and where is cholecalciferol (Vitamin D3) further modified?

Reaches liver via circulation; 25-hydroxylase produces 25-hydroxyvitamin D (calcidediol)

How & where is 25-hydroxyvitamin D further modified?

Reaches renal tubular epithelium via circulation or glomerular filtration; 1a-hydroxylase (CPY27B1) produces 1,25-dihydroxyvitamin D (calcitriol)

What type of receptor does parathyroid hormone bind to? Where is it expressed?

PTH receptor; Gs & Gq-linked GPCR

Expressed in osteoblasts & renal tubular epithelial cells

What type of receptor does calcitonin bind to? Where is it expressed?

Calcitonin receptor; Gs-linked GPCR

Expressed in osteoclasts & renal tubular epithelial cells

What type of receptor does calcitriol bind to? Where is it expressed?

Vitamin D receptor (VDR); nuclear hormone receptor

Expressed in osteoblasts, renal tubular epithelial cells, small intestinal epithelial cells, & principle cells.

Which hormones regulate Ca absorption? Via what mechanisms?

Calcitriol stimulates transcellular Ca absorption

• activation of receptor promotes gene transcription for Ca transporters (TrpV5/6, calbindin, & PMCA)

PTH stimulates transcellular Ca reabsorption

• Activation promotes activity of transporters

Calcitonin inhibits Ca reabsorption

• minor role, unknown mechanism

Which hormones regulate Pi absorption? Via what mechanisms?

PTH inhibits active, transcellular Pi reabsorption

• receptor activation inhibits activity of transporters

Calcitriol stimulates active, transcellular Pi reabsorption

• receptor activation promotes gene transcription for transporters (NPTs)

What factors do osteoblasts secrete that effect bone resorption?

Monocyte colony-stimulating factor(M-CSF)

• Binds and activates colony-stimulating factor-1 (C-FMS) on monocyte/macrophage progenitor cells

• promotes differentiation into preosteoclasts

Receptor activation of NF-kB ligand (RANKL)

• binds and activates RANK on preosteoclasts and osteoclasts

• Promotes preosteoclasts differentiation to osteoclasts

Osteoprotegerin (OPG)

• decoy receptor for RANKL

• Terminates bone resorption process

How does activation of the PTH receptor alter bone resorption?

Promotes M-CSF & RANKL secretion

Sustained high release = increased ECF [Ca] & [Pi]

Intermittent or low release = increased bone density

How does activation of the vitamin D receptor alter bone resorption?

Promotes RANKL synthesis

• more minor role compared to PTH

How does activation of the calcitonin receptor alter bone resorption?

Inhibits bone resorption

• decreased release of Ca & Pi from bone

The Calcium-Sensing receptor is what kind of receptor? Where is it expressed & what processes does it regulate?

Gq & Gi-linked GPCR

Expressed in parathyroid principle cells, thyroid parafollicular cells, & renal tubular epithelial cells

• activation allows Ca to regulate Ca homeostasis

What stimulates PTH synthesis?

None- basal secretion of PTH is high, all regulation is inhibitory

What inhibits PTH synthesis?

Ca & calcitriol

How does Ca regulate PTH?

Increased ECF [Ca] → increased CaSR activation → inhibition of preproPTH transcription & inhibition of secretory vesicles exocytosis

How does calcitriol regulate PTH?

Activation of calcitriol receptor inhibits proproPTH transcription and stimulates CaSR gene transcription

What stimulates Calcitriol synthesis?

PTH

What inhibits calcitriol synthesis?

Ca & calcitriol

How does PTH stimulate calcitriol synthesis?

Activation of PTH receptor stimulates 1a-hydroxylase transcription

How does Ca inhibit calcitriol synthesis?

Increased activation of CaSR inhibits 1a-hydroxylase transcription

• negative feedback-like mechanism

How does calcitriol inhibit calcitriol synthesis?

Activation of calcitriol receptor inhibits 1a-hydroxylase transcription & stimulates 24-hydroxylase transcription

• product feedback loop

What stimulates calcitonin synthesis?

Ca

What inhibits calcitonin synthesis?

?unkown?

How does Ca stimulate calcitonin synthesis?

Activation of CaSR on parafollicular cells stimulates calcitonin synthesis and secretion

What is involved with the initial hypocalcemic response?

Decreased signaling via CaSR

• increased Ca reabsorption

• Increased PTH secretion

What is involved with the later hypocalcemic response?

Decreased signaling via CaSR

• increased PTH synthesis

• increases 1a-hydroxylase (CYP1a) transcription → increased calcitriol synthesis

What could help determine the cause of hypocalcemic?

ECF [Pi]

• hypophosphatemia = calcitriol deficiency

• Hyperphosphatemia or normal = PTH deficiency