Calcium regulation Flashcards
What three main hormones regulation Ca?
PTH
vitamin D metabolites.
calcitonin
What do the three hormones act on?
Kidney, gut and bone
How is Ca2+ stored in the body?
99% in bone
Rest in the form of simple phosphate salts
What is the normal range of calcium? What states is this calcium in?
2.4-2.6mM
50% is ionised and exists as free calcium
~40% is reversibly bound to plasma proteins
~10% exists as inorganic complexes with anions, esp phosphate and citrate
What is Ca required for?
EC coupling
synaptic transmission
platelet aggregation&coagultion
IC messenger
What may cause hypocalcaemia?
Often the result of secondary hyperparathyroidism due to chronic kidney disease
Excess plasma protein in multiple myeloma – reduces free Ca2+
Alkalosis: increase in negative charge on plasma proteins; more Ca2+ binds to protein; Ca2+ falls
Normal value of IC Ca
0.1uM
What can hypocalcaemia lead to?
neuronal hyperexcitability → lowered Ca2+ renders membrane slightly depolarised so it is more easily excited, additionally, certain Na+ channels are activated at these depolarised potentials, increasing Na+ permeability → tetany, which begins in the limbs, and may progress to convulsions.
The QT interval of the ECG is prolonged, and eventually heart failure occurs.
Treatment of hypocalcaemia?
initial calcium infusion, and long-term vitamin D administration to boost intestinal absorption.
Causes of hypercalcaemia
Often the result of primary hyperparathyroidism due to MEN (multiple endocrine neoplasia)
Loss of protein in nephrotic syndrome increases free Ca2+
Acidosis: decrease negative charge on plasma proteins; less Ca2+ bound to protein → hypercalcaemia
What does hypercalcaemia lead to?
Reduces neuron excitability slowing CNS activity
Insoluble calcium salts cause urinary stones and calcification of renal soft tissue which impairs renal function.
The body attempts to excrete the excess calcium via urine → polyuria, which leads to dehydration, and the large amounts of Ca2+ passing through the kidney lead to kidney stones
Treatment of hypercalcaemia
pamidronate – a BISPHOSPHONATE used to treat osteoporosis
Bisphosphonates inhibit bone resorption mainly by action on osteoclasts. They form tight complexes with Ca2+ in the bone matrix, and are released slowly as bone is resorbed by osteoclasts, which are thus exposed to high concentrations of the drugs
Main hormone for raising Ca levels
PTH
What is PTH secreted from and in response to?
Chief cells of parathyroid in response to decreased plasma Ca
How do chief cells sense Ca2+ and release PTH?
Falling plasma Ca2+ is sensed by the G protein-coupled Ca2+-SR (calcium sensing receptor) on chief cells. This process also requires magnesium
The calcium sensing receptor is coupled to both Gq and Gi proteins.
When no Ca2+ binds, the Gi protein is activated, initiating an intracellular cascade which induces PTH secretion
When Ca2+ binds the Ca-SR, the Gq protein is activated → stimulates phospholipase C → → ultimately leads to the activation of PKC which inhibits release of granules containing PTH and PTH synthesis
PTH action
PTH exerts its physiological effects via activation of the GPCR, the PTH1R – it is coupled to both adenylyl cyclase and phospholipase C (Gs and Gq-coupled)
PTH1R found on plasma membrane of osteoblasts and cells of proximal and distal tubules
Effect of PTH on kidneys
Acts to increase Ca2+ reabsorption in the distal tubule, prevents phosphate reabsorption
PTH binds to PTH1R in proximal renal tubule epithelial cells → inhibition of Na+-PO43- co-transport, and thus phosphate reabsorption from the proximal tubule. This has two major effects:
Raise free plasma Ca2+ by stimulating Ca2+ mobilisation from bone.
Less phosphate is available for the Ca2+ to bind to, thus a higher concentration of free calcium in the plasma.
Increased Ca2+ reabsorption is also stimulated in the DTs and CD independently of Na+
Increases the activity of 1α hydroxylase and thus increases synthesis of the active vitamin D metabolite: vitamin (1,25) D3, which has a role that will further be explored
Action of PTH on bone
BIPHASIC
- Continuous stimulation = catabolic → leads to bone resorption → increase in plasma Ca2+
- Has effects on osteoblast receptors:
- Causes release of IL-6 which increased osteoclast activity & increases RANK-RANKL signalling which promotes differentiation of osteoclast precursors
- Intermittent stimulation : Anabolic → positive effects of bone volume and microarchitecture → leads to decrease in plasma Ca2+
What does vitamin D do to whole body Ca?
Raises it
Describe vitamin D metabolism
Vitamin D3 (cholecalciferol) can either be synthesised in the skin (under the influence of UV light) or absorbed from our diet. It is then transported to the liver where it undergoes 25-hydroxylation by one of 2 hepatic enzymes (CYP27A1 or CYP2R1) to form calcifediol. During transport through the circulation, it is bound to a carrier protein (DBP). The calcifediol-DBP complex passes through the glomerular filter and is scavenged from the primary urine by the apical megalin receptor of the PT. Here, calcifediol is 1α-hydroxylated to the active vitamin D metabolite, calcitriol.
What do most actions of vitamin D stem from?
The fact that it binds to vitamin D response elements (VDR) in nuclei of target cells
Actions of vit D on intestine
- stimulates absorption of Ca through both genomic and nongenomic mechanisms
- Ca enters microvllius of the intestinal epithelial cell through TRPV6
- binds calmodulin in the microvillus
- this is attached to brush bored myosin which moves the calcium to calbindin which is transported in endocytic vesicles to basolateral membrane where it leaves through Ca-ATPase
- vitamin D enhances this by inducing TRPV6, CaBP and Ca-ATPase, as well as increasing the amount of CaM bound to brush-border myosin in the brush border
Actions of vit D on the kidney?
Has TRPV5 and Ca-ATPase (like the intestine) → vitamin D increases activity, calbindin also induced by vitamin D → leads to reabsorption
Phosphate reabsorption is mediated at the brush border by sodium-dependent phosphate transporters which rely on the basolateral Na/K-ATPase to maintain Na+ gradient → it is not clear whether vitamin D regulates the expression or activities of these transporters (as it does in the intestine), although it is known that PTH block reabsorption
Effects of vitamin D on bone
Complex action result of direct and indirect effects
Net effect is to cause the increased flux of Ca into bone - this is due to the effect on the kidneys and GI system to increase reabsorption/absorption to increase plasma [Ca] which increases the available Ca to mineralize unmineralized osteoid
The direct effect is to mobilize Ca from bone; both osteoblast and osteoclast precursors have VDRs
Osteoblasts produce certain proteins; alkaline phosphatase, collagenase, plasminogen activator
Promotes development (with PTH) of osteoclasts from precursors, increasing the number of mature osteoclasts which can liberate Ca
The direct effect on bone contradicts the overall effect on bone which is to promote mineralization
