The full-length calcium-sensing receptor dampens the calcemic response to 1 ,25(OH)2 vitamin D3 in vivo independently of parathyroid hormone

Egbuna O, Quinn S, Kantham L, Butters R, Pang J, Pollak M, Goltzman D, Brown E. The full-length calcium-sensing receptor dampens the calcemic response to 1 ,25(OH)2 vitamin D3 in vivo independently of parathyroid hormone. Am J Physiol Renal Physiol 297: F720 –F728, 2009. First published May 27, 2009; doi:10.1152/ajprenal.00164.2009.—1 ,25(OH)2 vitamin D3 [1,25(OH)2D3] increases serum Ca concentration in vivo, an action counteracted by activation of the Ca -sensing receptor (CaSR), which decreases parathyroid hormone (PTH) secretion and increases renal Ca excretion. Relatively little is known of the role the CaSR plays in this response through its potentially direct actions in kidney, gut, and bone independently of PTH. We report PTH-independent roles of the CaSR in modulating the response to exogenous 1,25(OH)2D3 in mice with targeted disruption of both the CaSR and PTH genes (C P ) compared with that in mice with disruption of the PTH gene alone (C P ) or wild-type mice (C P ). After intraperitoneal injection of 0.5 ng/g body wt 1,25(OH)2D3, peak calcemic responses were observed at 24 h in all three genotypes in association with 1) a greater increase in serum Ca in C P mice than in the other genotypes on a Ca replete diet that was attenuated by a Ca -deficient diet and pamidronate, 2) increased urinary Ca -to-creatinine ratios (UCa/Cr) in the C P and C P mice but a lowered ratio in the C P mice on a Ca -replete diet, and 3) no increase in calcitonin (CT) secretion in the C P and C P mice and a small increase in the C P mice. PTH deficiency had the anticipated effects on the expression of key genes involved in Ca transport at baseline in the duodenum and kidney, and injection of 1,25(OH)2D3 increased gene expression 8 h later. However, the changes in the genes evaluated did not fully explain the differences in serum Ca seen among the genotypes. In conclusion, mice lacking the full-length CaSR have increased sensitivity to the calcemic action of 1,25(OH)2D3 in the setting of PTH deficiency. This is principally from enhanced 1,25(OH)2D3-mediated gut Ca absorption and decreased renal Ca excretion, without any differences in bone-related release of Ca or CT secretion among the three genotypes that could explain the differences in their calcemic responses.