Calcium-sensing receptor on parathyroid chief cells
Sensor / first step · Class C GPCR Gq/11 Cinacalcet
The calcium-sensing receptor is a class C G-protein-coupled receptor on the chief cell that reads ionised calcium directly. Occupancy by calcium inhibits PTH release, so a fall in calcium lifts the brake. The relation is a steep inverse sigmoid, which is why calcium is held in so narrow a range.
Traced from the start
- Fall in ionised calciumRise in ionised calcium
- Calcium-sensing receptor on parathyroid chief cells
Detail
- Receptor
- Class C GPCR signalling through Gq/11 and Gi; a rise in extracellular calcium raises intracellular calcium and inhibits PTH secretion, PTH gene transcription and chief-cell proliferation
- Also expressed
- Basolateral membrane of the thick ascending limb (high calcium there inhibits paracellular calcium reabsorption, causing hypercalciuria), thyroid C cells, gut and bone
- Magnesium
- Magnesium acts at the same receptor: mild hypomagnesaemia stimulates PTH, but severe hypomagnesaemia paralyses PTH secretion and causes end-organ PTH resistance
- Anatomy
- Four glands, from the third (which become the inferior glands, descending with the thymus) and fourth (superior) pharyngeal pouches; ectopic tissue is therefore found in the mediastinum
- Drug
- Cinacalcet is a calcimimetic, an allosteric activator that makes the receptor more sensitive to calcium and so lowers PTH and calcium
When it goes wrong
Heterozygous inactivating CASR mutation: familial hypocalciuric hypercalcaemia
Lifelong mild hypercalcaemia with a normal or mildly raised PTH and a urinary calcium:creatinine clearance ratio below 0.01; benign, and parathyroidectomy must be avoided
Activating CASR mutation: autosomal dominant hypocalcaemia
Hypocalcaemia with a low or inappropriately normal PTH and hypercalciuria; treating with calcium and vitamin D provokes nephrocalcinosis
Total thyroidectomy or anterior neck surgery devascularising the glands
Hypocalcaemia within 24-72 hours with perioral paraesthesia, positive Chvostek and Trousseau signs and a prolonged QT interval
22q11.2 deletion (DiGeorge syndrome)
Failed development of the third and fourth pharyngeal pouches: neonatal hypocalcaemic seizures, thymic aplasia and conotruncal cardiac defects
Practise this structure
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