Endocrinology and Metabolism


The calcium-sensing receptor (CaSR) controls parathyroid hormone (PTH) secretion, which, in turn, via direct and indirect actions on kidney, bone, and intestine, maintains a normal extracellular ionized calcium concentration (Ca2+o). There is less understanding of the CaSR's homeostatic importance outside of the parathyroid gland. We have employed single and double knockout mouse models, namely mice lacking PTH alone (CaSR+/+ PTH−/−, referred to as C+P), lacking both CaSR and PTH (CaSR−/− PTH−/−, CP) or wild-type (CaSR+/+ PTH+/+, C+P+) mice to study CaSR-specific functions without confounding CaSR-mediated changes in PTH. The mice received three hypercalcemic challenges: an oral Ca2+ load, injection or constant infusion of PTH via osmotic pump, or a phosphate-deficient diet. CP mice show increased susceptibility to developing hypercalcemia with all three challenges compared with the other two genotypes, whereas C+P mice defend against hypercalcemia similarly to C+P+ mice. Reduced renal Ca2+ clearance contributes to the intolerance of the CP mice to Ca2+ loads, as they excrete less Ca2+ at any given Ca2+o than the other two genotypes, confirming the CaSR's direct role in regulating renal Ca2+ handling. In addition, C+P+ and C+P, but not CP, mice showed increases in serum calcitonin (CT) levels during hypercalcemia. The level of 1,25(OH)2D3 in CP mice, in contrast, was similar to those in C+P and C+P+ mice during an oral Ca2+ load, indicating that increased 1,25(OH)2D3 production cannot account for the oral Ca2+-induced hypercalcemia in the CP mice. Thus, CaSR-stimulated PTH release serves as a “floor” to defend against hypocalcemia. In contrast, high-Ca2+o-induced inhibition of PTH is not required for a robust defense against hypercalcemia, at least in mice, whereas high-Ca2+o-stimulated, CaSR-mediated CT secretion and renal Ca2+ excretion, and perhaps other factors, serve as a “ceiling” to limit hypercalcemia resulting from various types of hypercalcemic challenges.

  • serum calcium
  • calcitonin
  • kidney
  • vitamin D
  • urinary calcium
  • diuretic
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