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

Author

Listed:
  • 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)

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.

Suggested Citation

  • Patricia P. Centeno & Amanda Herberger & Hee-Chang Mun & Chialing Tu & Edward F. Nemeth & Wenhan Chang & Arthur D. Conigrave & Donald T. Ward, 2019. "Phosphate acts directly on the calcium-sensing receptor to stimulate parathyroid hormone secretion," Nature Communications, Nature, vol. 10(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-12399-9
    DOI: 10.1038/s41467-019-12399-9
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    Cited by:

    1. Yulong Gong & Bingyuan Yang & Dingdong Zhang & Yue Zhang & Zihan Tang & Liu Yang & Katie C. Coate & Linlin Yin & Brittney A. Covington & Ravi S. Patel & Walter A. Siv & Katelyn Sellick & Matthew Shou , 2023. "Hyperaminoacidemia induces pancreatic α cell proliferation via synergism between the mTORC1 and CaSR-Gq signaling pathways," Nature Communications, Nature, vol. 14(1), pages 1-19, December.

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