Calcium Homeostasis Flashcards
Describe the biological functions of calcium
- skeletal rigidity - hydroxyapatite and calcium phosphate
- component of connective tissue and teeth
- haemostasis (blood clotting) - intrinsic and extrinsic cascades
- excitation-contraction coupling - smooth and striated muscle
- stimulus-secretion coupling - ACh from the NMJ
- cell-to-cell adhesion - cadherins
- second messenger for enzymatic activity (calmodulin)
What hormones regulate extracellular calcium levels
Parathyroid hormone,1,25-dihydroxyvitamin D, Calcitonin
Origin and function of 1,25-dihydroxyvitamin D
Kidneys; increases small intestine ability to intake calcium in diet
Origin and function of PTH
Cheif cells of parathyroid glands; acts on bones to increase release of calcium, increases reaborption of calcium from filtrate, facilitates conversion of vit D -> 1,25-dihydroxyvitamin D (biologically active
Functions of calcitonin
- respond to hypercalcemia
- stores calcium in skeleton
Stimuli for secretion of PTH
Hypocalcaemia
Action of PTH on bones to induce hypercalcemia
PTH stimulates cytokines that recruit osteoblasts, which induce osteoclasts (bone resorption)
Action of PTH on GI tract to induce hypercalcemia
Activates synthesis of 1,25-dihydroxyvitamin D (kidney) and increases trancellular uptake of Ca from the small intestine
Action of PTH on kidneys to induce hypercalcemia
Increase calcium reabsoprtion by increasing activity of calcium channels and pumps. Synthesis of 1,25-dihydroxyvitamin D
How is free calcium sensed
Calcium-sensing receptors (CaSR)
Synthesis of PTH in hypercalcemia
Negative feedback pathway suppresses PTH secretion
PTH action on 1,25-dihydroxyvitamin D
increases formation by increasing hydroxylation to 1,25-dihydroxyvitamin D in the kidney
The role of 1,25-dihydroxyvitamin D on the small intestine
- diffuses into enterocytes and binds to vitamin D receptor (VDR) and increases gene expression
- increases calcium transport across the enterocyte membrane by increased expression of apical calcium channels and basolateral calcium transporters
The role of 1,25-dihydroxyvitamin D on the kidneys
Increases expression of Na-Pi cotransporter and improves PTH-mediated calcium absorption
Role of 1,25-dihydroxyvitamin D on the bones
Increases number of osteoclasts
Stages of 1,25-dihydroxyvitamin D hydroxylation
- 1st occurs in skin where UV light converts 7-dehydrocholesterol into cholecalciferol (vitamin D3)
- 2nd occurs in the liver where cholecalciferol is converted to biologically inactive 25-hydroxycholecalciferol
- Final reaction occurs in kidneys where it is converted to 1,25-dihydroxyvitamin D, which aids absorption across the intestinal wall
How is the second hydroxylation of 1,25-dihydroxyvitamin D regulated
- increased GH
- increased prolactin
- increased oestrogen
- decreased FGF23
- decreased 1,25-dihydroxyvitamin D
What action does increased 1,25-diOH-D3 in kidneys have on PTH
Inhibitory
Heterozygous CaSR and Galpha11 gain-of-function mutation in ADH
Causes high urinary excretion of calcium even in normal extracellular calcium concentrations (hypocalcemia)
Heterozygous inactivating mutation in the calcium-sensing receptor (CaSR) results in
Hypercalcemia -> no inhibition of PTH secretion even when plasma calcium concentration is high
Origin and function of calcitonin
Clear cells of the thyroid glands; responds to hypercalcaemia (function is limited in healthy individuals)
- PRIMARY STIMULUS FOR THE RELEASE OF PTH
Calcitonin is secreted in response to
High plasma calcium concentration
Action of STIM1
- Responds to calcium store depletion by oligomerising and translocating to the plasma membrane
- Bind to Orai and open calcium channels to replenish intracellular calcium
Inhibitor of STIM1
Calmodulin
Symptoms of hypercalcemia
(bones, stones, groans and psychiatric overtones)
- lethargy
- depression
- constipation
- renal calculi
- frequent urination
- nausea
- arrhythmias
Symptoms of hypoclacemia
- pins and needles
- muscle spasms
- paralysis
- convulsions
How sex hormones influence calcium homeostasis
Oestrogen is repsonsible fo bone maturation and testosterone maintains bone density
How glucocorticoids maintain calcium homeostasis
Regulate bone density and intestinal calcium absorption
How parathyroid hormone-related protein (PTHrP) influences calcium homeostasis
mimics action of PTH in bones and kdineys -> produces outside of parathyroid glands
- induces hypercalcemia mostly by paracrine rather than endocrine signalling
