The full-length calcium-sensing receptor dampens the calcemic response to 1alpha,25(OH)2 vitamin D3 in vivo independently of parathyroid hormone.
1Alpha,25(OH)(2) vitamin D(3) [1,25(OH)(2)D(3)] increases serum Ca(2+) concentration in vivo, an action counteracted by activation of the Ca(2+)-sensing receptor (CaSR), which decreases parathyroid hormone (PTH) secretion and increases renal Ca(2+) 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)(2)D(3) 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)(2)D(3), peak calcemic responses were observed at 24 h in all three genotypes in association with 1) a greater increase in serum Ca(2+) in C(-)P(-) mice than in the other genotypes on a Ca(2+)-replete diet that was attenuated by a Ca(2+)-deficient diet and pamidronate, 2) increased urinary Ca(2+)-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(2+)-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(2+) transport at baseline in the duodenum and kidney, and injection of 1,25(OH)(2)D(3) increased gene expression 8 h later. However, the changes in the genes evaluated did not fully explain the differences in serum Ca(2+) seen among the genotypes. In conclusion, mice lacking the full-length CaSR have increased sensitivity to the calcemic action of 1,25(OH)(2)D(3) in the setting of PTH deficiency. This is principally from enhanced 1,25(OH)(2)D(3)-mediated gut Ca(2+) absorption and decreased renal Ca(2+) excretion, without any differences in bone-related release of Ca(2+) or CT secretion among the three genotypes that could explain the differences in their calcemic responses.
Egbuna
Ogo
O
Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. ogo.egbuna@gmail.com
Quinn
Steven
S
Kantham
Lakshmi
L
Butters
Robert
R
Pang
Jiang
J
Pollak
Martin
M
Goltzman
David
D
Brown
Edward
E
D000818:Animals; D002116:Calcitonin / Q000378:metabolism; D002118:Calcium / Q000097:blood / Q000378:metabolism* / Q000652:urine; D002136:Calcium, Dietary / Q000008:administration & dosage / Q000378:metabolism; D003404:Creatinine / Q000652:urine; D004164:Diphosphonates / Q000494:pharmacology; D004386:Duodenum / Q000187:drug effects / Q000378:metabolism*; D004872:Ergocalciferols / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D005786:Gene Expression Regulation; D005838:Genotype; D007274:Injections, Intraperitoneal; D007408:Intestinal Absorption; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D000077268:Pamidronate; D010281:Parathyroid Hormone / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D044169:Receptors, Calcium-Sensing / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D002136:Calcium, Dietary; D004164:Diphosphonates; D004872:Ergocalciferols; D010281:Parathyroid Hormone; D044169:Receptors, Calcium-Sensing; C003564:1,25-dihydroxyergocalciferol; D002116:Calcitonin; D003404:Creatinine; D000077268:Pamidronate; D002118:Calcium