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

Patricia P. Centeno, Amanda Herberger, Hee-Chang Mun, Chialing Tu, Edward F. Nemeth, Wenhan Chang, Arthur D. Conigrave and Donald T. Ward ()
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Patricia P. Centeno: The University of Manchester
Amanda Herberger: UCSF Department of Veterans Affairs Medical Center
Hee-Chang Mun: University of Sydney, School of Life and Environmental Sciences
Chialing Tu: UCSF Department of Veterans Affairs Medical Center
Edward F. Nemeth: MetisMedica, 13 Poplar Plains Road
Wenhan Chang: UCSF Department of Veterans Affairs Medical Center
Arthur D. Conigrave: University of Sydney, School of Life and Environmental Sciences
Donald T. Ward: The University of Manchester

Nature Communications, 2019, vol. 10, issue 1, 1-12

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-019-12399-9

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