Calcium homeostasis: hormonal regulation Flashcards
Extracellular Ca 2+ is required for
nerve function muscle contraction coagulation skeletal mineralization activation of most cell types (signalling pathways)
Physiologically active fraction of total plasma calcium is that which is
unbound
Forms of calcium in the blood plasma
15 % : complexes with anions eg lactate, sulfate. Diffusable, bu biologically inert
40%: bound to albumin (proteins)- non-diffusable, remains in BVs
45% : unbound ‘ionised’ fraction. Diffusable and biologically active
which hormones control calcium homeostasis
calcitriol, calcitonon and parathyroid hormone
PTH
Single chain PP
Derived from larger precursor peptides pre-proPTH and proPTH
PTH produced by
chief cells of PT gland
PTH half life
10 min
Normal plasma level
10-55 pg/ml (picogram per ml)
Regulation of PTH minute to minute
Ca 2+ acting via the G protein coupled calcium sensing receptor (CaSR)
Decr in ionized (free) plasma Ca2+ causes incr in PTH secretion
Long term regulation of PTH
1,25(OH)2D3 acts directly on PTG to decr preproPTH mRNA
Actions of PTH
increases plasma Ca 2+ ( and decr plasma PO4 3-) via kidney, bone and GI tract
Kidney (PTH)
- stimulates Ca2+ reabsorption in the distal tubule
- Inhibits PO4 3- reabsorption in the proximal tubule
- Incr production of 1,25-(OH)2D3, which increases intestinal absorption of Ca and PO4
Bone (PTH)
- stimulates rapid efflux (out) of Ca2+ from freely exchangeable calcium pool (an effect on osteocytes and bone-lining cells)
- Incr number and activity of osteoclasts (resorp) via action on osteoblasts
GI tract (PTH)
-stimulates absorption of CA2+ and PO43-
effect delayed and indirect (incr renal production of 1,25 (OH)2 D3 )
Summary of regulation of Calcium by PTH
Decr plasma CA triggers incr PTH secretion
Effect on bone: incr bone resorption
Effect on kidney: decr phosphate reabsorption, incr Ca reabsorption, incr hydroxylation of 25 OH vtamin D
Intestines: Incr Ca absorption (indirect via 1,25- dihydroxycholecalicferol)
Lead to incr in plasma Ca back to normal
1a, 25- dihydroxyvitamin D3 -calcitriol
Abbrev to 1,25(OH)2D3
Active metabolite of vitamin D3
A secosteroid (open B ring)
Produced in kidney by: 1 alpha hydroxylation of 25(OH)D3
Bulk bound to vit D- binding protein (alpha-globulin) transcalferin
Only free fraction is active: half life 3-6h
Interacts with a nuclear receptor- member of the nuclear receptor superfamily
1,25(OH)2D3 production
Vit D3 (cholecalciferol), whether dietary or synthesised in the skin, is rapidly converted in the liver to 25(OH)D3 (by action of 25-hydroxylase) then into 1,25 Dihydroxyvitamin D3 in the kidney by action of 1a-hydroxylase
Plasma levels of 1,25(OH)2D3 are determined by
rate of conversion of 25(OH)D3 to 1,25(OH)2 D3 (activation)
Rate of conversion of 1,25 (OH)2D3 to 24,25 (OH)2 D3 (inactivation)
Actions of 1,25 (OH)2D3
Increases plasma Ca via GI tract, bone and kidney
GI tract (main) 1,25
Stimulates absorption of Ca (mainly in the duodenum)
Stimulates absorption of PO43- (jejunum and ileum)
Bone 1,25
Incr number and activity of osteoclasts
Leads to incr in bone resorption and hence incr in CA2+ and PO43- release
Kidney 1,25
faciltates Ca2+ resorption (DCT)
Calcitonin (CT)
single chain pp
Selected by parafollicular C cells of thyroid gland
Secretion regulated by Ca2+(incr CA = incr CT secretion) and gastrin incr
Actions lead to a fall in plasma Ca- opposite effect to PTH
Calcitonin action on bone
decr release of CA and PO4
Decr rapid efflux across the bone membrane
Acts directly on osteoclasts to inhibit resorption
calcitonin action on kidney
decr tubular reabsorption of CA and PO4
Calcitonin action on GI tract
no sigfig effect on Ca absorption in small intestine
Exact physiological role of Calcitonin in humans
uncertain
- may protect against postprandial hypercalcaemia
- may protect female skeleton during pregnancy and lactation
- in pathological states may act to prevent excessive bone destruction
overview of regulation of Ca homeostasis
high Ca, thyroid gland releases calcitonin, stimulates calcium deposition in bones
low Ca, PTGs release PTH, effect of PTH on bones, kidneys and GI tract results in higher Ca levels
hypercalcaemia
associated with excess PTH
eg rumour of PTG
affects bones, kidneys GI tract as well as neurological symptoms
hypocalcaemia
PTH resistance- no effect
Lack of vitamin D effect
symptom related to neuromuscular excitability
Long term lack of vitamin D affects bone growth
eg osteoporosis
endocrine regulation of Ca homeostasis summary
decreased blood Ca stimulates PTH secretion from PTG
PTH stimulates osteoclasts to break down bone and release Ca
in the kidneys- PTH increases Ca reabsorption and stimulates vitamin D formation
Vitamin D promotes Ca absorption from the small intestine into the blood
Increased Ca stimulates calcitonin secretion from thyroid gland
Calcitonin inhibits osteoclasts, which allows for enhanced osteoblasts uptake of Ca from blood into bone
bone structure
made up of several cell types surrounded by a collagen matrix called osteoid, upon which are deposited minerals eg crystals of calcium, phosphate
Where are PTG’s
in the neck
Are PTGs endocrine/exocrine
endocrine
Vitamin D3
cholecaliferol
Formed from action of UV on a cholesterol derivative in the skin (7-dehydrocholesterol)
cholecalciferol names
Vitamin D3
Calcifediol names
25-Hydroxyvitamin D3
25(OH)D3
Calcitriol
1,25-dihydroxyvitamin D3
1,25-(OH)2D3
