The calcium-sensing receptor (CaSR) defends against hypercalcemia independently of its regulation of parathyroid hormone secretion

Kantham L, Quinn SJ, Egbuna OI, Baxi K, Butters R, Pang JL, Pollak MR, Goltzman D, Brown EM. The calcium-sensing receptor (CaSR) defends against hypercalcemia independently of its regulation of parathyroid hormone secretion. Am J Physiol Endocrinol Metab 297: E915-E923, 2009. First published July 28, 2009; doi:10.1152/ajpendo.00315.2009.-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 (Ca-o(2+)). 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-/-, C-P-) 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. C-P- 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 C-P- 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 C-P-, mice showed increases in serum calcitonin (CT) levels during hypercalcemia. The level of 1,25(OH)(2)D-3 in C-P- 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)(2)D-3 production cannot account for the oral Ca2+-induced hypercalcemia in the C-P- mice. Thus, CaSR-stimulated PTH release serves as a floor to defend against hypocalcemia. In contrast, high-Ca-o(2+)-induced inhibition of PTH is not required for a robust defense against hypercalcemia, at least in mice, whereas high-Ca-o(2+)-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.