The calcium-sensing receptor is required for normal calcium homeostasis independent of parathyroid hormone
Claudine H. Kos, … , Theresa A. Guise, Martin R. Pollak
Claudine H. Kos, … , Theresa A. Guise, Martin R. Pollak
Published April 1, 2003
Citation Information: J Clin Invest. 2003;111(7):1021-1028. https://doi.org/10.1172/JCI17416.
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Article Genetics

The calcium-sensing receptor is required for normal calcium homeostasis independent of parathyroid hormone

Abstract

The extracellular calcium-sensing receptor (CaR; alternate gene names, CaR or Casr) is a membrane-spanning G protein–coupled receptor. CaR is highly expressed in the parathyroid gland, and is activated by extracellular calcium (Ca2+o). Mice homozygous for null mutations in the CaR gene (CaR–/–) die shortly after birth because of the effects of severe hyperparathyroidism and hypercalcemia. A wide variety of functions have been attributed to CaR. However, the lethal CaR-deficient phenotype has made it difficult to dissect the direct effect of CaR deficiency from the secondary effects of hyperparathyroidism and hypercalcemia. We therefore generated parathyroid hormone–deficient (PTH-deficient) CaR–/– mice (Pth–/–CaR–/–) by intercrossing mice heterozygous for the null CaR allele with mice heterozygous for a null Pth allele. We show that genetic ablation of PTH is sufficient to rescue the lethal CaR–/– phenotype. Pth–/–CaR–/– mice survive to adulthood with no obvious difference in size or appearance relative to control Pth–/– littermates. Histologic examination of most organs did not reveal abnormalities. These Pth–/–CaR–/– mice exhibit a much wider range of values for serum calcium and renal excretion of calcium than we observe in control littermates, despite the absence of any circulating PTH. Thus, CaR is necessary for the fine regulation of serum calcium levels and renal calcium excretion independent of its effect on PTH secretion.

Authors

Claudine H. Kos, Andrew C. Karaplis, Ji-Bin Peng, Matthias A. Hediger, David Goltzman, Khalid S. Mohammad, Theresa A. Guise, Martin R. Pollak

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Expression levels of CaT1 and CaT2/ECaC are altered in Pth–/–CaR–/– mice...
Expression levels of CaT1 and CaT2/ECaC are altered in Pth–/–CaR–/– mice relative to control littermates. The mRNA expression levels of CaT1 (black bars) and CaT2/ECaC (white bars) in the duodenum and kidney were assessed by real-time quantitative PCR and normalized against GAPDH mRNA levels. We compared expression in RNA samples from three pairs of sex-matched littermates maintained on high-calcium diets (2% calcium, top) and three pairs of sex-matched littermates on regular diets (0.81% calcium, bottom). We performed assays in duplicate for each RNA sample. Renal CaT1 and CaT2/ECaC expression were consistently higher in CaR-deficient mice, regardless of diet (mean increased expression of 65% and 60%, respectively). These differences reached statistical significance with P = 0.015 and P = 0.0025, respectively, in paired t tests. Intestinal CaT1 expression was highly variable. In animals fed high-calcium diets as well as those fed regular diets, the overall trend was toward increased CaT1 expression in the CaR-deficient animals, but this trend did not reach statistical significance either when the groups were analyzed separately according to diet or when all six pairs were analyzed together.