L53 - Calcium Homeostasis

• What is Calcium homeostasis?

  How the amount of Ca in the body/bloodstream is regulated.
• What is Calcium?

  
  

  How must we gain it?

  - Most abundant mineral in body.

  
  

  - 99% in skeleton.

  
  

  - Can't be produced by biological processes, so muct be gained from diet.

  
• How is Calcium distributed in the blood?

  - 40% protein-bound so can't diffuse through cell membranes.

  
  

  - Free ionised: only ionised Ca is physiologically active and can be used by the body.

  
• List some functions of Calcium.

  - Neurotransmitter release.

  
  

  - Muscle contraction.

  
  

  - Blood clotting (factor VI formation).

  
  

  - Skeletal mineralisation.

  
  

  - Cell signalling (2nd messenger/ion channel activation).

  
  

  - Cellular metabolism.

  
• What is extracellular [Ca2+] conc determined by?

  Interplay betweenabsorptionbyintestine,excretionbykidney, anduptake/releasebybones.

  
  

  Distribution of Ca in body is from exchange betweenboneandextracellularfluid.

  
• Which 3 hormones affect Calcium homeostasis?

  1)Parathyroidhormone. (PTH)

  2)Calcitriol(active vit D3).

  3)Calcitonin.
• Where is Parathyroid hormone produced?

  
  

  What is PTH derived from?

  By chief cells of parathyroid gland (x4).

  
  

  Derived from Pre-ProPTH precursor which gets cleaved.

  
• What do the parathyroid glands (x4) do?

  Release PTH which regulates Calcium and Phosphate levels.

  
• How is PTH secretion regulated?

  GPCR is activated by Ca binding - results in inhibition of PTH secretion.

  
  

  - A decrease in ionised, free plasma [Ca] causes an increase in PTH secretion.

  
  

  - PTH is released when blood [Ca] levels fall (short term).

  
• How is PTH secretion regulated/decreased long term?

  Calcitriol (active D3) acts directly on parathyroid gland cells to decrease preproPTH mRNA.

  
  

  Decreases PTH synthesis by lessening the amount of its precursor.

  
• What happens in the parathyroid gland when plasma [Ca] decreases?

  Ca not able to bind to CaSRs (Calcium Sensing Receptor) on parathyroid gland, so PTH secretion increases.

  
• What's the effect of increased PTH secretion on bone?

  Increased bone resorption

  
• What's the effect of increased PTH secretion on kidneys?

  - Decreased phosphate reabsorption.

  
  

  - Increased Ca2+ reabsorption.

  
  

  - Increased hydroxylation of 25-OH vitamin D.

  
• How does increased PTH secretion indirectly affect intestines?

  Increased Ca2+ absorption

  
• How does PTH increase plasma [Ca] via the kidneys?

  
  

  And decrease phosphate?

  
  

  What's the net effect of this?

  - Instructs kidneys to absorb more Ca back from urine.

  - Stimulates Ca2+ reabsorption in DCT.

  - Inhibits phosphate reabsorption in PCT.

  - Increases activity of 1a-hydroxylase and decreases 2,4-hydroxylase.

  Net effect =increase in renally produced Calcitriol.

  Less Ca and more phosphate excreted.
• How does PTH affect bone?

  
  

  What's the net effect?

  - Activates osteoclasts (bone resorbing cells), releasing Ca into blood from stores.

  - Stimulates Ca2+ efflux from freely exchangeable Ca pool.

  - Increases no. and activity of osteoclasts via osteoblast action.

  - Indirectly stimulates osteoclast differentiation, increasing bone resorption.- Demineralisation results in Ca movement out of bone and into blood stream.

  Net effect= Increase in bone resorption, so increase in Ca2+ and phosphate release.
• How does PTH affect the GI tract?

  Indirectly - increases renal calcitriol production.

  
  

  - Stimulates absorption of Ca and phosphate from diet.

  
  

  - Delayed effect (>24hrs).

  
  

  - Changes vit D into D3 (active form), helping intestines absorb Ca from food.
• Which type of vitamin D do we get from UV? What's its precursor?

  Precursor = 7-Dehydrocholesterol.

  
  

  = Cholecalciferol (D3) from sun.
• What's the difference between vitamin D2 and D3?

  
  

  What are they also known as?

  D2(ergocalciferol) is derived from plants, andD3(colecalciferol) is derived from animals.

  
• What happens to vitamin D (fat soluble) in the body?

  
  

  Where?

  
  

  By what enzymes?

  Colecalciferol is converted to25(OH) colecalciferol/calcidiol) in the liver by vit D25-hydroxylase.

  This is converted to1,25(OH)2 Colecalciferolin the kidneys by vit D1a-hydroxylase.

  
• How is colecalciferol (D3) obtained?

  - Formed in skin from UV.

  
  

  - Or from cholesterol derivative, 7-dehydroxycholesterol.

  
• How is ergocalciferol (D2) obtained?

  From diet

  
• What are the 2 steps in metabolism to form active D3?

  
  

  What are the additional groups? Where are they added in the body?

  
  

  What is the product also called?

  - 1st hydroxyl group added in liver, catalysed by 25(OH)hydroxylase.

  - 2nd hydroxyl group added in kidney. Catalysed by 1a-hydroxylase.

  
  

  Product =Calcitriol!

  
• What is Calcitriol? Why is it considered a hormone?

  1a,25-dihydroxyvitamin D3.

  - Hormone bc actively synthesised in body.

  - Active metabolite of vitamin D3.
• What is transcalferin?

  - Specialised vit D receptor with both hormone and DNA- binding.

  
  

  - Once vit D is bound, intracellular receptors function as transcription factors and modulate gene expression.
• How is Calcitriol production regulated?

  - vit D is rapidly converted in liver to Calcidiol.

  
  

  - PTH stimulates activity of 1a-hydroxylase, increasing calcitriol formation.

  
• What can inhibit 1a-hydroxylase activity?

  Increased phosphate levels.

  
• What are Calcitriol levels determined by?

  Activation= rate of conversion of calcidiol to calcitriol

  
  

  Inactivation= rate of conversion ofcalcitriolto calcitrioic acid.

  
• What does Calcitriol do in the GI tract?

  - Stimulates Ca2+ absorption (duodenum).

  
  

  - Stimulates phosphate absorption (jejunum + ileum).
• Why is dietary Ca2+ not absorbed sufficiently in the absence of vitamin D?

  Bc Calcitriol is needed to stimulate Ca absorption in small intestine (mainly duodenum).
• What does calcitriol do to bones?

  - Increases no. and activity of osteoclasts.

  
  

  - Increases bone resorption, so...

  
  

  - Increases release of Ca/phosphate from bone.
• What does calcitriol do to the kidney?

  - Facilitates Ca2+ reabsorption in DCT, reducing amount of Ca being excreted.
• What does calcitriol do to calcitronin?

  Calcitriol inhibits the release of Calcitonin (which has opposite effects to PTH and Calcitriol).
• Where is Calcitonin secreted from? What regulates secretion?

  - From parafollicular C cells of thyroid glands.

  
  

  - Secretion regulated by Ca2+.

  
  

  Increase Ca = increased Calcitonin secretion.

  
• What does calcitonin do?

  Decreases plasma [Ca] - opposite effect to PTH.

  
• What does Calcitonin do to the bone?

  - Inhibits osteoclasts, so decreases resorption.

  
  

  - Decreases efflux of Ca and phosphate from bone.

  
  

  - Indirectly increased osteoblast activity (bc coupled w/osteoblasts.
• What does calcitonin do to the kidney?

  Decreases tubular reabsorption of Ca + phosphate.
• What does calcitonin do in the intestine?

  No significant effect.
• Describe the physiological role of Calcitonin.

  May:

  - protect against postprandial hypercalcaemia (after a meal!).

  
  

  - Protects female skeleton in pregnancy and lactation.

  
  

  - Prevent excessive bone destruction in disease.

  
  

  - Indirectly inhibit bone resorption and release prolactin (PRL) from pituitary gland.

  
• What hormone is released when plasma [Ca2+] is low?

  Parathyroid hormone.