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

• Published in: Nature communications Vol. 10; no. 1; pp. 4693 - 12
• Main Authors: Centeno, Patricia P, Herberger, Amanda, Mun, Hee-Chang, Tu, Chialing, Nemeth, Edward F, Chang, Wenhan, Conigrave, Arthur D, Ward, Donald T
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 16.10.2019; Nature Publishing Group UK; Nature Portfolio
• Subjects: Animals; Binding sites; Calcium; Calcium-sensing receptors; Detection; Disease control; Gene Knockout Techniques; HEK293 Cells; Humans; Hyperparathyroidism; Hyperparathyroidism, Secondary - etiology; Hyperparathyroidism, Secondary - metabolism; Kidney diseases; Menopause; Mice; Mutation; Parathyroid; Parathyroid gland; Parathyroid Glands - metabolism; Parathyroid hormone; Parathyroid Hormone - metabolism; Phosphate; Phosphates; Phosphates - metabolism; Receptors, Calcium-Sensing - genetics; Receptors, Calcium-Sensing - metabolism; Renal function; Renal Insufficiency, Chronic - complications; Renal Insufficiency, Chronic - metabolism; Secretion; Vitamin D
• ISSN: 2041-1723; 2041-1723
• 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.