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Gene Review

Casr  -  calcium-sensing receptor

Mus musculus

Synonyms: CaR, CaSR, Extracellular calcium-sensing receptor, Gprc2a, PCaR1, ...
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Disease relevance of Casr


High impact information on Casr

  • Mice lacking the calcium-sensing receptor (Casr) were created to examine the receptor's role in calcium homeostasis and to elucidate the mechanism by which inherited human Casr gene defects cause diseases [1].
  • Finally, in a three-dimensional culture system that recapitulates the lactating alveolus, activation of the basolateral CaR increases transcellular calcium transport independent of its effect on PTHrP [6].
  • The CaR becomes expressed on mammary epithelial cells at the transition from pregnancy to lactation [6].
  • CaR is highly expressed in the parathyroid gland, and is activated by extracellular calcium (Ca(2+)(o)) [7].
  • 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 [7].

Chemical compound and disease context of Casr


Biological context of Casr

  • We screened a mouse genomic library with a Casr-rs1 probe and identified two additional Casr-related sequences (Casr-rs2 and Casr-rs3) [10].
  • We mapped Casr-rs1 to mouse Chromosome (Chr) 7 by interspecific backcross analysis, whereas the known Casr localizes to mouse Chr 16 [10].
  • We show that genetic ablation of PTH is sufficient to rescue the lethal CaR(-/-) phenotype [7].
  • DNA sequence analysis revealed the presence of a Gprc2a missense mutation, Leu723Gln [4].
  • Inheritance studies of Nuf mice revealed that the trait was transmitted in an autosomal-dominant manner, and mapping studies located the locus to chromosome 16, in the vicinity of the CaSR gene (Mouse Genome Database symbol Gprc2a) [4].

Anatomical context of Casr

  • We then evaluated the changes in epidermal keratinocyte morphology and differentiation in Casr(-/-) mice lacking the full-length CaR [11].
  • A calcium-sensing receptor (Casr) belonging to the metabotropic glutamate family of G-protein-coupled receptors (GPCR) that transduces the effects of extracellular calcium in the parathyroid gland as well as other tissues has been identified [10].
  • Taken together, it is possible that osteoblasts may recognize extracellular calcium via CaSR and regulate osteoclastogenesis [12].
  • The present study was performed to determine whether bone marrow cells express the CaR, since cells within the marrow space could be exposed to substantial changes in Ca2+e related to bone turnover [13].
  • CaR agonists also stimulated DNA synthesis in C3HT10(1/2) fibroblasts, but not in mesangial PVG, CHO, hepatic HTC, COS-7 cells, or malignant transformed ROS17/2.8 and UMR-106 osteoblasts [14].

Associations of Casr with chemical compounds

  • When E1 cells stimulated with agonists of CaSR, gadolinium, and neomycin, OPGL/ODF mRNA expression decreased [12].
  • We found that CaR agonists, calcium (Ca2+), gadolinium (Gd3+), aluminum (Al3+), and neomycin, stimulated DNA synthesis in murine-derived MC3T3-E1 preosteoblasts, whereas magnesium (Mg2+), nickel (Ni2+), cadmium (Cd2+), and zinc (Zn2+) had no effect [14].
  • Exposure of ST2 cells to high Ca2+(o) (4.8 mM) or to the polycationic CaR agonists, neomycin (300 microM) or gadolinium (100 microM), stimulated both chemotaxis and DNA synthesis in ST2 cells [5].
  • We first confirmed that Gd(3+) activated the CaSR by measuring intracellular Ca(2+) concentration ([Ca(2+)](i)) in CALs loaded with fura 2 [15].
  • The calcium sensing receptor (CaSR) has emerged as an important mediator of a wide range of Ca(2+)-dependent physiological responses (Ca(2+) signaling) in various tissues [16].

Physical interactions of Casr


Regulatory relationships of Casr

  • To explore the role of CaSR in the epidermis, we utilised the keratin 14 promoter to express CaSR cDNA constitutively in the basal cells of the stratified squamous epithelium of transgenic mice [16].
  • BACKGROUND: The calcium sensing receptor (CaSR) regulates serum calcium by suppressing secretion of parathyroid hormone; it also regulates renal tubular calcium excretion [2].
  • Physiological studies in heterozygous calcium sensing receptor (CaSR) gene-ablated mice confirm that the CaSR regulates calcitonin release in vivo [2].

Other interactions of Casr

  • Thyroid C-cells (which make calcitonin) express CaSR and may, therefore, be regulated by it [2].
  • 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 [7].
  • The loss of the full-length CaR altered the morphologic appearance of the epidermis and resulted in a reduction of the mRNA and protein levels of the keratinocyte differentiation marker, loricrin [19].
  • Our study examines whether extracellular cations stimulate osteoblasts through the recently identified G protein-coupled calcium receptor (CaR) [14].
  • In addition, a substantial fraction (approximately 60%) of low density murine marrow cells cultured for 1 week at 4.8 mM Ca2+e expressed both CaR immunoreactivity and nonspecific esterase, an enzyme expressed by monocyte/macrophages and fibroblasts [13].

Analytical, diagnostic and therapeutic context of Casr


  1. A mouse model of human familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Ho, C., Conner, D.A., Pollak, M.R., Ladd, D.J., Kifor, O., Warren, H.B., Brown, E.M., Seidman, J.G., Seidman, C.E. Nat. Genet. (1995) [Pubmed]
  2. Physiological studies in heterozygous calcium sensing receptor (CaSR) gene-ablated mice confirm that the CaSR regulates calcitonin release in vivo. Fudge, N.J., Kovacs, C.S. BMC Physiol. (2004) [Pubmed]
  3. Regulation of murine fetal-placental calcium metabolism by the calcium-sensing receptor. Kovacs, C.S., Ho-Pao, C.L., Hunzelman, J.L., Lanske, B., Fox, J., Seidman, J.G., Seidman, C.E., Kronenberg, H.M. J. Clin. Invest. (1998) [Pubmed]
  4. Activating calcium-sensing receptor mutation in the mouse is associated with cataracts and ectopic calcification. Hough, T.A., Bogani, D., Cheeseman, M.T., Favor, J., Nesbit, M.A., Thakker, R.V., Lyon, M.F. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  5. Extracellular calcium (Ca2+(o))-sensing receptor in a murine bone marrow-derived stromal cell line (ST2): potential mediator of the actions of Ca2+(o) on the function of ST2 cells. Yamaguchi, T., Chattopadhyay, N., Kifor, O., Brown, E.M. Endocrinology (1998) [Pubmed]
  6. The calcium-sensing receptor regulates mammary gland parathyroid hormone-related protein production and calcium transport. VanHouten, J., Dann, P., McGeoch, G., Brown, E.M., Krapcho, K., Neville, M., Wysolmerski, J.J. J. Clin. Invest. (2004) [Pubmed]
  7. The calcium-sensing receptor is required for normal calcium homeostasis independent of parathyroid hormone. Kos, C.H., Karaplis, A.C., Peng, J.B., Hediger, M.A., Goltzman, D., Mohammad, K.S., Guise, T.A., Pollak, M.R. J. Clin. Invest. (2003) [Pubmed]
  8. Functional importance of the Ala(116)-Pro(136) region in the calcium-sensing receptor. Constitutive activity and inverse agonism in a family C G-protein-coupled receptor. Jensen, A.A., Spalding, T.A., Burstein, E.S., Sheppard, P.O., O'Hara, P.J., Brann, M.R., Krogsgaard-Larsen, P., Bräuner-Osborne, H. J. Biol. Chem. (2000) [Pubmed]
  9. Relationship between parathyroid calcium-sensing receptor expression and potency of the calcimimetic, cinacalcet, in suppressing parathyroid hormone secretion in an in vivo murine model of primary hyperparathyroidism. Kawata, T., Imanishi, Y., Kobayashi, K., Kenko, T., Wada, M., Ishimura, E., Miki, T., Nagano, N., Inaba, M., Arnold, A., Nishizawa, Y. Eur. J. Endocrinol. (2005) [Pubmed]
  10. Identification of putative transmembrane receptor sequences homologous to the calcium-sensing G-protein-coupled receptor. Hinson, T.K., Damodaran, T.V., Chen, J., Zhang, X., Qumsiyeh, M.B., Seldin, M.F., Quarles, L.D. Genomics (1997) [Pubmed]
  11. Epidermal expression of the full-length extracellular calcium-sensing receptor is required for normal keratinocyte differentiation. Komuves, L., Oda, Y., Tu, C.L., Chang, W.H., Ho-Pao, C.L., Mauro, T., Bikle, D.D. J. Cell. Physiol. (2002) [Pubmed]
  12. Low calcium environment effects osteoprotegerin ligand/osteoclast differentiation factor. Takeyama, S., Yoshimura, Y., Shirai, Y., Deyama, Y., Hasegawa, T., Yawaka, Y., Kikuiri, T., Matsumoto, A., Fukuda, H. Biochem. Biophys. Res. Commun. (2000) [Pubmed]
  13. Expression of an extracellular calcium-sensing receptor in human and mouse bone marrow cells. House, M.G., Kohlmeier, L., Chattopadhyay, N., Kifor, O., Yamaguchi, T., Leboff, M.S., Glowacki, J., Brown, E.M. J. Bone Miner. Res. (1997) [Pubmed]
  14. A distinct cation-sensing mechanism in MC3T3-E1 osteoblasts functionally related to the calcium receptor. Quarles, L.D., Hartle, J.E., Siddhanti, S.R., Guo, R., Hinson, T.K. J. Bone Miner. Res. (1997) [Pubmed]
  15. Calcium-sensing receptor regulation of PTH-dependent calcium absorption by mouse cortical ascending limbs. Motoyama, H.I., Friedman, P.A. Am. J. Physiol. Renal Physiol. (2002) [Pubmed]
  16. Overexpression of the calcium sensing receptor accelerates epidermal differentiation and permeability barrier formation in vivo. Turksen, K., Troy, T.C. Mech. Dev. (2003) [Pubmed]
  17. p44/42 MAPK activation is necessary for receptor activator of nuclear factor-kappaB ligand induction by high extracellular calcium. Kim, Y.H., Kim, J.M., Kim, S.N., Kim, G.S., Baek, J.H. Biochem. Biophys. Res. Commun. (2003) [Pubmed]
  18. A novel cation-sensing mechanism in osteoblasts is a molecular target for strontium. Pi, M., Quarles, L.D. J. Bone Miner. Res. (2004) [Pubmed]
  19. The calcium sensing receptor and its alternatively spliced form in murine epidermal differentiation. Oda, Y., Tu, C.L., Chang, W., Crumrine, D., Kömüves, L., Mauro, T., Elias, P.M., Bikle, D.D. J. Biol. Chem. (2000) [Pubmed]
  20. Extracellular Mg2(+)- and Ca2(+)-sensing in mouse distal convoluted tubule cells. Bapty, B.W., Dai, L.J., Ritchie, G., Jirik, F., Canaff, L., Hendy, G.N., Quamme, G.A. Kidney Int. (1998) [Pubmed]
  21. Expression and signal transduction of calcium-sensing receptors in cartilage and bone. Chang, W., Tu, C., Chen, T.H., Komuves, L., Oda, Y., Pratt, S.A., Miller, S., Shoback, D. Endocrinology (1999) [Pubmed]
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