The calcium-sensing receptor is required for normal calcium homeostasis independent of parathyroid hormone.
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 (Ca(2+)(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.
Kos
Claudine H
CH
Renal Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
Karaplis
Andrew C
AC
Peng
Ji-Bin
JB
Hediger
Matthias A
MA
Goltzman
David
D
Mohammad
Khalid S
KS
Guise
Theresa A
TA
Pollak
Martin R
MR
D000483:Alleles; D000818:Animals; D001835:Body Weight; D002118:Calcium / Q000097:blood / Q000378:metabolism*; D018076:DNA, Complementary / Q000378:metabolism; D005838:Genotype; D006579:Heterozygote; D006706:Homeostasis; D006720:Homozygote; D066298:In Vitro Techniques; D007668:Kidney / Q000378:metabolism; D051379:Mice; D010281:Parathyroid Hormone / Q000378:metabolism / Q000502:physiology*; D010641:Phenotype; D044169:Receptors, Calcium-Sensing; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D018076:DNA, Complementary; D010281:Parathyroid Hormone; D044169:Receptors, Calcium-Sensing; D011956:Receptors, Cell Surface; D002118:Calcium