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

Nat Commun. 2019 Oct 16;10(1):4693. doi: 10.1038/s41467-019-12399-9.


Extracellular phosphate regulates its own renal excretion by eliciting concentration-dependent 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Gene Knockout Techniques
  • HEK293 Cells
  • Humans
  • Hyperparathyroidism, Secondary / etiology
  • Hyperparathyroidism, Secondary / metabolism
  • Mice
  • Mutation
  • Parathyroid Glands / metabolism*
  • Parathyroid Hormone / metabolism*
  • Phosphates / metabolism*
  • Receptors, Calcium-Sensing / genetics
  • Receptors, Calcium-Sensing / metabolism*
  • Renal Insufficiency, Chronic / complications
  • Renal Insufficiency, Chronic / metabolism


  • CASR protein, human
  • CASR protein, mouse
  • Parathyroid Hormone
  • Phosphates
  • Receptors, Calcium-Sensing