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Abstract: FR-PO488

Hyperphosphatemia Is a Negative Modulator of the Calcium-Sensing Receptor

Session Information

Category: Bone and Mineral Metabolism

  • 401 Bone and Mineral Metabolism: Basic


  • Pacios centeno, Patricia, The University of Manchester, Manchester, United Kingdom
  • Tu, Chia-Ling, San Francisco VA Medical Center, San Francisco, California, United States
  • Herberger, Amanda L., University of California, San Francisco/ San Francisco Veterans Affairs Medical Center, San Francsicso, California, United States
  • Chang, Wenhan, Endocrine Unit, SF-VAMC, University of California San Francisco, San Francisco, California, United States
  • Conigrave, Arthur D., University of Sydney, Sydney, New South Wales, Australia
  • Ward, Donald T,, University of Manchester, Manchester, United Kingdom

Group or Team Name

  • Ward

Chronic kidney disease (CKD) is associated with hyperphosphataemia and secondary hyperparathyroidism (SHPT). The key controller of parathyroid hormone (PTH) secretion is the calcium-sensing receptor (CaSR), whose crystallised extracellular domain has revealed four putative phosphate-binding sites in its inactive conformation. Our aim was to determine whether extracellular phosphate, at concentrations found in CKD, can inhibit CaSR and increase PTH secretion, and thus potentially contribute to the aetiology of SHPT.


CaSR activity was measured as Ca2+i mobilisation (Fura-2) and extracellular signal-regulated kinase (ERK) phosphorylation in HEK-293 cells stably transfected with human CaSR. The HEPES buffer contained 0.5mM CaCl2 with phosphate added as Na2HPO4 and KH2PO4 in a 4:1 ratio (pH 7.4). PTH secretion was measured in dispersed human parathyroid cells obtained ethically following neck surgery and in cultures of intact mouse parathyroid glands.


Raising phosphate concentration from 0.8 mM (physiological) to 2 mM (CKD-like) inhibited CaSR-induced Ca2+i mobilisation (-52 ± 4%; P<0.001) and ERK activation (-18 ± 3%; P<0.01). Raised phosphate concentration (2 mM) inhibited the maximal (Emax) Ca2+o response suggesting non-competitive antagonism (-32 ± 3%; P<0.001). Further, phosphate attenuated CaSR activity with an IC50 of 1.2 mM (95%CI 1.0 to 1.4). Mutation of CaSRR62 (a putative phosphate-binding site) to alanine ablated this inhibitory effect. Finally, pathophysiologic phosphate concentrations elicited rapid (within minutes) and reversible increases in PTH secretion in freshly-isolated human parathyroid cells (+39 ± 10%, 0.8 vs 2mM, P<0.05; +58 ± 15%, 0.8 vs 3mM; P<0.001) consistent with a receptor-mediated action (with thanks to Ryan Mun). Similarly, in cultures of mouse parathyroid glands phosphate again elicited rapid, concentration-dependent increases in PTH secretion (by up to 180%, 3 vs 0.8mM).


Therefore CaSR is able to sense pathophysiologic deviations in phosphate concentration apparently via non-competitive antagonism at CaSRR62 resulting in increased PTH secretion. This mechanism may help explain the contribution of hyperphosphatemia to SHPT.


  • Other NIH Support