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This Article Full Text Full Text (PDF) All Versions of this Article: 297/4/E915    most recent 00315.2009v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Kantham, L. Articles by Brown, E. M. PubMed PubMed Citation Articles by Kantham, L. Articles by Brown, E. M.

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

¹Division of Endocrinology, Diabetes and Hypertension, and ²Renal Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts; and ³Calcium Research Laboratory and Department of Medicine, McGill University Health Centre and McGill University, Montreal, Quebec, Canada

Submitted 15 May 2009 ; accepted in final form 22 July 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 (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^–/–, 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)₂D₃ 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)₂D₃ 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-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