Phosphate acts directly on the calcium-sensing receptor to stimulate parathyroid hormone secretion

Patricia Centeno, Amanda Herberger, Hee-Chang Mun, Chialing Tu, Edward F. Nemeth, Wenhan Chang, Arthur D. Conigrave, Donald Ward

Research output: Contribution to journalArticlepeer-review


Extracellular phosphate regulates its own renal excretion by eliciting concentration-dependent secretion of parathyroid hormone (PTH). How- ever, 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.
Original languageEnglish
Article number4693
Number of pages12
JournalNature Communications
Publication statusPublished - 16 Oct 2019


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