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

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

doi:10.1038/s41467-019-12399-9

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.

Highlights

Extracellular phosphate regulates its own renal excretion by eliciting concentrationdependent secretion of parathyroid hormone (PTH)
By increasing extracellular Pi, at concentrations observed in chronic kidney disease (CKD), we demonstrate that hyperphosphatemia inhibits the calcium-sensing receptor (CaSR) in a noncompetitive manner and increases PTH secretion
By combining in vitro signaling experiments with ex vivo PTH secretion measurements from human and KO Casr murine parathyroid glands, we reveal that Pi acts as a noncompetitive antagonist of the CaSR at pathophysiological concentrations, resulting in increased PTH secretion

Summary

Introduction

Extracellular phosphate regulates its own renal excretion by eliciting concentrationdependent secretion of parathyroid hormone (PTH). The calcium-sensing receptor (CaSR) represents the key controller of PTH secretion and is expressed abundantly in parathyroid glands and in renal tubules. Pi excretion in the renal proximal tubule, eliminating the released Pi and so permitting ionized Ca2oþ concentration to rise that feeds back on the parathyroid glands to inhibit further PTH secretion[2,3]. Parathyroid glands and bone can sense increased extracellular Pi, by an unknown mechanism, and respond by secreting PTH and fibroblast growth factor 23 (FGF23) respectively, which increase renal excretion of Pi9–14. In SHPT, chronic underactivation of the CaSR permits continuously elevated levels of PTH secretion causing chronic dloysssf1u5n–1c8ti.oInn oaf stshoeciCataio2oþn homeostatic system and with SHPT, increased profound bone Ca × P product contributes to vascular calcification and eventual heart disease, calciphylaxis (tissue necrosis), and renal osteodystrophy[19,20]

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Conclusion