Faculty Opinions recommendation of Phosphate acts directly on the calcium-sensing receptor to stimulate parathyroid hormone secretion.

Extracellular phosphate regulates its own renal excretion by eliciting concentrationdependent secretion of parathyroid hormone (PTH).However, the phosphate-sensing mechanism remains unknown and requires elucidation for understanding the aetiology of secondary hyperparathyroidism in chronic kidney disease (CKD).The calcium-sensing receptor (CaSR) is the main controller of PTH secretion and here we show that raising phosphate concentration within the pathophysiologic range for CKD significantly inhibits CaSR activity via non-competitive antagonism.Mutation of residue R62 in anion binding site-1 abolishes phosphate-induced inhibition of CaSR.Further, pathophysiologic phosphate concentrations elicit rapid and reversible increases in PTH secretion from freshly-isolated human parathyroid cells consistent with a receptor-mediated action.The same effect is seen in wild-type murine parathyroid glands, but not in CaSR knockout glands.By sensing moderate changes in extracellular phosphate concentration, the CaSR represents a phosphate sensor in the parathyroid gland, explaining the stimulatory effect of phosphate on PTH secretion.