calcium sensing receptors


Summary: A class of G-protein-coupled receptors that react to varying extracellular CALCIUM levels. Calcium-sensing receptors in the PARATHYROID GLANDS play an important role in the maintenance of calcium HOMEOSTASIS by regulating the release of PARATHYROID HORMONE. They differ from INTRACELLULAR CALCIUM-SENSING PROTEINS which sense intracellular calcium levels.

Top Publications

  1. Peiris D, Pacheco I, Spencer C, Macleod R. The extracellular calcium-sensing receptor reciprocally regulates the secretion of BMP-2 and the BMP antagonist Noggin in colonic myofibroblasts. Am J Physiol Gastrointest Liver Physiol. 2007;292:G753-66 pubmed
    ..Together, our data suggest that the CaSR mediates the effective concentration of BMP-2 in the intestine, which leads to enhanced repair and barrier development. ..
  2. Hu J, Spiegel A. Structure and function of the human calcium-sensing receptor: insights from natural and engineered mutations and allosteric modulators. J Cell Mol Med. 2007;11:908-22 pubmed
  3. Chiu W, Chen H, Chao H, Yann L, Tsai K. Identification of three novel mutations in the GATA3 gene responsible for familial hypoparathyroidism and deafness in the Chinese population. J Clin Endocrinol Metab. 2006;91:4587-92 pubmed
    ..Our results expand the spectrum of mutations and report the first splice donor site mutation of the GATA3 gene. In contrast, we do not find causal sequence variants of the CaSR gene from our collection of familial hypoparathyroidism. ..
  4. Brown E. Clinical lessons from the calcium-sensing receptor. Nat Clin Pract Endocrinol Metab. 2007;3:122-33 pubmed
    ..Finally, calcimimetics-allosteric activators of the CaR-treat secondary hyperparathyroidism effectively in end-stage renal failure. ..
  5. Bustamante M, Hasler U, Leroy V, de Seigneux S, Dimitrov M, Mordasini D, et al. Calcium-sensing receptor attenuates AVP-induced aquaporin-2 expression via a calmodulin-dependent mechanism. J Am Soc Nephrol. 2008;19:109-16 pubmed
  6. Justinich C, Mak N, Pacheco I, Mulder D, Wells R, Blennerhassett M, et al. The extracellular calcium-sensing receptor (CaSR) on human esophagus and evidence of expression of the CaSR on the esophageal epithelial cell line (HET-1A). Am J Physiol Gastrointest Liver Physiol. 2008;294:G120-9 pubmed
    ..We conclude that the CaSR is present on basal cells of the human esophagus and is present in a functional manner on the esophageal epithelial cell line, HET-1A. ..
  7. Huang Y, Zhou Y, Yang W, Butters R, Lee H, Li S, et al. Identification and dissection of Ca(2+)-binding sites in the extracellular domain of Ca(2+)-sensing receptor. J Biol Chem. 2007;282:19000-10 pubmed
  8. Kelly C, Gunn I, Gaffney D, Devgun M. Serum calcium, urine calcium and polymorphisms of the calcium sensing receptor gene. Ann Clin Biochem. 2006;43:503-6 pubmed
    ..6%; EE, 0%. Biochemical parameters in these individuals were not statistically different from the wild type. The increase in serum ionized calcium in the AS group was small and, therefore, unlikely to be of clinical significance. ..
  9. Hu J, Reyes Cruz G, Goldsmith P, Gantt N, Miller J, Spiegel A. Functional effects of monoclonal antibodies to the purified amino-terminal extracellular domain of the human Ca(2+) receptor. J Bone Miner Res. 2007;22:601-8 pubmed
    ..Recombinant antibodies with antigen binding domains of 5C8 and 1A8 could be useful in the treatment of hyperparathyroidism and osteoporosis, respectively. ..

More Information


  1. Kapoor A, Satishchandra P, Ratnapriya R, Reddy R, Kadandale J, Shankar S, et al. An idiopathic epilepsy syndrome linked to 3q13.3-q21 and missense mutations in the extracellular calcium sensing receptor gene. Ann Neurol. 2008;64:158-67 pubmed publisher
  2. Lomonte C, Vernaglione L, Chimienti D, Bruno A, Cocola S, Teutonico A, et al. Does vitamin D receptor and calcium receptor activation therapy play a role in the histopathologic alterations of parathyroid glands in refractory uremic hyperparathyroidism?. Clin J Am Soc Nephrol. 2008;3:794-9 pubmed publisher
    ..This study was aimed to assess a possible association between histopathologic changes of parathyroid tissue and treatment modality...
  3. Macleod R, Hayes M, Pacheco I. Wnt5a secretion stimulated by the extracellular calcium-sensing receptor inhibits defective Wnt signaling in colon cancer cells. Am J Physiol Gastrointest Liver Physiol. 2007;293:G403-11 pubmed
    ..Our findings demonstrate that APC status plays a key role as a determinant of Wnt5a secretion and suggest that CaSR-mediated secretion of Wnt5a will inhibit defective Wnt signaling in APC-truncated cells in an autocrine manner. ..
  4. Vezzoli G, Terranegra A, Arcidiacono T, Biasion R, Coviello D, Syren M, et al. R990G polymorphism of calcium-sensing receptor does produce a gain-of-function and predispose to primary hypercalciuria. Kidney Int. 2007;71:1155-62 pubmed
    ..0001). Our findings indicate that R990G polymorphism results in a gain-of-function of the calcium-sensing receptor and increased susceptibility to primary hypercalciuria. ..
  5. Fryer R, Segreti J, Widomski D, Franklin P, Banfor P, Koch K, et al. Systemic activation of the calcium sensing receptor produces acute effects on vascular tone and circulatory function in uremic and normal rats: focus on central versus peripheral control of vascular tone and blood pressure by cinacalcet. J Pharmacol Exp Ther. 2007;323:217-26 pubmed
    ..Moreover, subsequent mechanistic studies suggest that increases in MAP produced by cinacalcet may be mediated by reduced tonic NO synthase-dependent NO production subsequent to reductions in blood iCa2+. ..
  6. Berra Romani R, Raqeeb A, Laforenza U, Scaffino M, Moccia F, Avelino Cruz J, et al. Cardiac microvascular endothelial cells express a functional Ca+ -sensing receptor. J Vasc Res. 2009;46:73-82 pubmed publisher
    ..These data provide evidence that CMEC express CaSR, which is able to respond to physiological agonists by mobilizing Ca(2+) from intracellular InsP(3)-sensitive stores. ..
  7. Zhang W, Fu S, Lu F, Wu B, Gong D, Pan Z, et al. Involvement of calcium-sensing receptor in ischemia/reperfusion-induced apoptosis in rat cardiomyocytes. Biochem Biophys Res Commun. 2006;347:872-81 pubmed
    ..In conclusion, these results suggest that CaR is involved in the induction of cardiomyocyte apoptosis during ischemia/reperfusion through activation of cytochrome c-caspase-3 signaling pathway. ..
  8. Scillitani A, Guarnieri V, Battista C, De Geronimo S, Muscarella L, Chiodini I, et al. Primary hyperparathyroidism and the presence of kidney stones are associated with different haplotypes of the calcium-sensing receptor. J Clin Endocrinol Metab. 2007;92:277-83 pubmed
    ..Our data indicate that the CASR SRQ haplotype is significantly associated with PHPT in our population. Within the PHPT patient population, the AGQ haplotype is significantly associated with kidney stones. ..
  9. Woo S, Song H, Song K, Kim D, Lee K, Kim S, et al. A case report of familial benign hypocalciuric hypercalcemia: a mutation in the calcium-sensing receptor gene. Yonsei Med J. 2006;47:255-8 pubmed
    ..A heterozygous mutation of E297K (GAG --> AAG, exon 4) of CaSR gene was found in 3 family members. To our knowledge, it is the first confirmed case of FBHH with CaSR gene mutation in Korea. ..
  10. Drueke T, Martin D, Rodriguez M. Can calcimimetics inhibit parathyroid hyperplasia? Evidence from preclinical studies. Nephrol Dial Transplant. 2007;22:1828-39 pubmed
  11. März W, Seelhorst U, Wellnitz B, Tiran B, Obermayer Pietsch B, Renner W, et al. Alanine to serine polymorphism at position 986 of the calcium-sensing receptor associated with coronary heart disease, myocardial infarction, all-cause, and cardiovascular mortality. J Clin Endocrinol Metab. 2007;92:2363-9 pubmed
    ..001) and PTH (P < 0.02), and lower phosphate (P < 0.003) in CAD patients and controls. Serine at position 986 of CASR may be an independent genetic predictor of angiographic CAD, previous MI, and cardiovascular mortality. ..
  12. Mamillapalli R, VanHouten J, Zawalich W, Wysolmerski J. Switching of G-protein usage by the calcium-sensing receptor reverses its effect on parathyroid hormone-related protein secretion in normal versus malignant breast cells. J Biol Chem. 2008;283:24435-47 pubmed publisher
    ..Because PTHrP contributes to hypercalcemia and bone metastases, switching of G-protein usage by the CaR may contribute to the pathogenesis of breast cancer. ..
  13. Bouschet T, Martin S, Henley J. Regulation of calcium-sensing-receptor trafficking and cell-surface expression by GPCRs and RAMPs. Trends Pharmacol Sci. 2008;29:633-9 pubmed publisher
  14. Awumey E, Howlett A, Putney J, Diz D, Bukoski R. Ca(2+) mobilization through dorsal root ganglion Ca(2+)-sensing receptor stably expressed in HEK293 cells. Am J Physiol Cell Physiol. 2007;292:C1895-905 pubmed
    ..9 +/- 5.2% (at 1 mM Ca(2+)) and 40.5 +/- 6.5% (at 2 mM Ca(2+)), compared with controls. The findings suggest involvement of PKC in the pathway for Ca(2+) mobilization following CaR activation. ..
  15. Gavalas N, Kemp E, Krohn K, Brown E, Watson P, Weetman A. The calcium-sensing receptor is a target of autoantibodies in patients with autoimmune polyendocrine syndrome type 1. J Clin Endocrinol Metab. 2007;92:2107-14 pubmed
    ..023). No CaSR antibodies could be detected in any patients or controls using a radiobinding assay. The CaSR is an autoantigen in APS1, but detection of antibodies against the receptor appears to be influenced by the assay system used. ..
  16. Mizobuchi M, Ogata H, Hatamura I, Saji F, Koiwa F, Kinugasa E, et al. Activation of calcium-sensing receptor accelerates apoptosis in hyperplastic parathyroid cells. Biochem Biophys Res Commun. 2007;362:11-6 pubmed
    ..These results suggest that CaR activation by R-568 accelerates parathyroid cell death, probably through an apoptotic mechanism in uremic rats in vitro. ..
  17. Ortiz Capisano M, Ortiz P, Garvin J, Harding P, Beierwaltes W. Expression and function of the calcium-sensing receptor in juxtaglomerular cells. Hypertension. 2007;50:737-43 pubmed
    ..We conclude that juxtaglomerular cells express the calcium-sensing receptor and that their activation leads to inhibition of adenylyl cyclase-V activity, decreasing cAMP formation and suppressing renin release. ..
  18. Kawata T, Imanishi Y, Kobayashi K, Onoda N, Okuno S, Takemoto Y, et al. Direct in vitro evidence of the suppressive effect of cinacalcet HCl on parathyroid hormone secretion in human parathyroid cells with pathologically reduced calcium-sensing receptor levels. J Bone Miner Metab. 2006;24:300-6 pubmed
    ..Data from this in vitro analysis support the clinical application of cinacalcet in PHPT and SHPT therapy. ..
  19. Makita N, Sato J, Manaka K, Shoji Y, Oishi A, Hashimoto M, et al. An acquired hypocalciuric hypercalcemia autoantibody induces allosteric transition among active human Ca-sensing receptor conformations. Proc Natl Acad Sci U S A. 2007;104:5443-8 pubmed
    ..We thus speculate that physiological modulators may exist that enable an agonist to specifically activate only one signaling pathway via a GPCR that activates multiple signaling pathways. ..
  20. Lorenz S, Frenzel R, Paschke R, Breitwieser G, Miedlich S. Functional desensitization of the extracellular calcium-sensing receptor is regulated via distinct mechanisms: role of G protein-coupled receptor kinases, protein kinase C and beta-arrestins. Endocrinology. 2007;148:2398-404 pubmed
    ..In contrast, GRK 2 predominantly interferes with G protein-mediated inositol-1,4,5-trisphosphate formation by binding to G alpha(q). ..
  21. Phillips C, Harnett M, Chen W, Smith S. Calcium-sensing receptor activation depresses synaptic transmission. J Neurosci. 2008;28:12062-70 pubmed publisher
    ..In summary, reduced CaSR function enhanced synaptic transmission and CaSR stimulation had the opposite effect. Thus CaSR provides a mechanism that may compensate for the fall in release probability that accompanies decreases in [Ca](o). ..
  22. Chang W, Tu C, Cheng Z, Rodriguez L, Chen T, Gassmann M, et al. Complex formation with the Type B gamma-aminobutyric acid receptor affects the expression and signal transduction of the extracellular calcium-sensing receptor. Studies with HEK-293 cells and neurons. J Biol Chem. 2007;282:25030-40 pubmed
  23. Wettschureck N, Lee E, Libutti S, Offermanns S, Robey P, Spiegel A. Parathyroid-specific double knockout of Gq and G11 alpha-subunits leads to a phenotype resembling germline knockout of the extracellular Ca2+ -sensing receptor. Mol Endocrinol. 2007;21:274-80 pubmed
    ..Our results demonstrate the critical role of both Gq and G11 in mediating inhibition of PTH secretion by extracellular Ca2+. ..
  24. Harding B, Curley A, Hannan F, Christie P, Bowl M, Turner J, et al. Functional characterization of calcium sensing receptor polymorphisms and absence of association with indices of calcium homeostasis and bone mineral density. Clin Endocrinol (Oxf). 2006;65:598-605 pubmed
  25. Cheng Z, Tu C, Rodriguez L, Chen T, Dvorak M, Margeta M, et al. Type B gamma-aminobutyric acid receptors modulate the function of the extracellular Ca2+-sensing receptor and cell differentiation in murine growth plate chondrocytes. Endocrinology. 2007;148:4984-92 pubmed
    ..These results support the idea that physical interactions between CaRs and GABA-B-R1s modulate the growth and differentiation of GPCs, potentially by altering the function of CaRs. ..
  26. Bhagavathula N, Kelley E, Reddy M, Nerusu K, Leonard C, Fay K, et al. Upregulation of calcium-sensing receptor and mitogen-activated protein kinase signalling in the regulation of growth and differentiation in colon carcinoma. Br J Cancer. 2005;93:1364-71 pubmed
    ..They appear to function, at least in part, independently of one another. ..
  27. Silve C, Petrel C, Leroy C, Bruel H, Mallet E, Rognan D, et al. Delineating a Ca2+ binding pocket within the venus flytrap module of the human calcium-sensing receptor. J Biol Chem. 2005;280:37917-23 pubmed
    ..Altogether, these data define a Ca(2+) binding pocket within the CaSR VFTM that may be conserved in several other class III GPCRs, thereby providing a molecular basis for extracellular Ca(2+) sensing by these receptors. ..
  28. Warner J, Epstein M, Sweet A, Singh D, Burgess J, Stranks S, et al. Genetic testing in familial isolated hyperparathyroidism: unexpected results and their implications. J Med Genet. 2004;41:155-60 pubmed
    ..Also apparent is the need for further investigation to identify additional genes associated with FIHP. ..
  29. Hofer A. Another dimension to calcium signaling: a look at extracellular calcium. J Cell Sci. 2005;118:855-62 pubmed
    ..The extracellular space might therefore constitute a much more dynamic Ca(2+) signaling compartment than previously appreciated. ..
  30. Silver J, Kilav R, Naveh Many T. Mechanisms of secondary hyperparathyroidism. Am J Physiol Renal Physiol. 2002;283:F367-76 pubmed
    ..PT trans factors and cis elements have been defined. ..
  31. Hu J, Spiegel A. Naturally occurring mutations of the extracellular Ca2+-sensing receptor: implications for its structure and function. Trends Endocrinol Metab. 2003;14:282-8 pubmed
  32. Rothe H, Shapiro W, Sun W, Chou S. Calcium-sensing receptor gene polymorphism Arg990Gly and its possible effect on response to cinacalcet HCl. Pharmacogenet Genomics. 2005;15:29-34 pubmed
  33. Parekh A, Putney J. Store-operated calcium channels. Physiol Rev. 2005;85:757-810 pubmed
  34. Tfelt Hansen J, Hansen J, Smajilovic S, Terwilliger E, Haunso S, Sheikh S. Calcium receptor is functionally expressed in rat neonatal ventricular cardiomyocytes. Am J Physiol Heart Circ Physiol. 2006;290:H1165-71 pubmed
    ..A specific calcium-sensing receptor on cardiac myocytes could play a role in regulating cardiac development, function, and homeostasis. ..
  35. Vargas Poussou R, Huang C, Hulin P, Houillier P, Jeunemaitre X, Paillard M, et al. Functional characterization of a calcium-sensing receptor mutation in severe autosomal dominant hypocalcemia with a Bartter-like syndrome. J Am Soc Nephrol. 2002;13:2259-66 pubmed
  36. Nemeth E. Calcimimetic and calcilytic drugs: just for parathyroid cells?. Cell Calcium. 2004;35:283-9 pubmed
  37. Brown E. Is the calcium receptor a molecular target for the actions of strontium on bone?. Osteoporos Int. 2003;14 Suppl 3:S25-34 pubmed
  38. Tfelt Hansen J, Chattopadhyay N, Yano S, Kanuparthi D, Rooney P, Schwarz P, et al. Calcium-sensing receptor induces proliferation through p38 mitogen-activated protein kinase and phosphatidylinositol 3-kinase but not extracellularly regulated kinase in a model of humoral hypercalcemia of malignancy. Endocrinology. 2004;145:1211-7 pubmed
    ..These effects are likely direct without the involvement of PTHrP in an autocrine mode. ..
  39. Kifor O, McElduff A, Leboff M, Moore F, Butters R, Gao P, et al. Activating antibodies to the calcium-sensing receptor in two patients with autoimmune hypoparathyroidism. J Clin Endocrinol Metab. 2004;89:548-56 pubmed
  40. Fuleihan G. Familial benign hypocalciuric hypercalcemia. J Bone Miner Res. 2002;17 Suppl 2:N51-6 pubmed
    ..In general, in view of the benign nature of FBHH, no particular intervention is needed except reassurance and counseling against parathyroidectomy. ..
  41. Kos C, Karaplis A, Peng J, Hediger M, Goltzman D, Mohammad K, et al. The calcium-sensing receptor is required for normal calcium homeostasis independent of parathyroid hormone. J Clin Invest. 2003;111:1021-8 pubmed
    ..Thus, CaR is necessary for the fine regulation of serum calcium levels and renal calcium excretion independent of its effect on PTH secretion. ..
  42. Breitwieser G, Miedlich S, Zhang M. Calcium sensing receptors as integrators of multiple metabolic signals. Cell Calcium. 2004;35:209-16 pubmed
    b>Calcium sensing receptors are critical to maintenance of organismal Ca2+ homeostasis, translating small changes in serum Ca2+ into changes in PTH secretion by the parathyroid glands and Ca2+ excretion by the kidneys...
  43. Mayer A, Ploix C, Orgiazzi J, Desbos A, Moreira A, Vidal H, et al. Calcium-sensing receptor autoantibodies are relevant markers of acquired hypoparathyroidism. J Clin Endocrinol Metab. 2004;89:4484-8 pubmed
    ..In conclusion, using an immunoblotting assay, we demonstrate the presence of CaSR aAbs in about one third of the patients with isolated AH, pointing out the value of detecting such aAbs to assess the autoimmune origin of the disease. ..
  44. Mun H, Franks A, Culverston E, Krapcho K, Nemeth E, Conigrave A. The Venus Fly Trap domain of the extracellular Ca2+ -sensing receptor is required for L-amino acid sensing. J Biol Chem. 2004;279:51739-44 pubmed
    ..The findings support the concept that the mGlu-1 amino acid binding site for L-glutamate is conserved as an L-amino acid binding site in its homolog, the CaR. ..
  45. Petrel C, Kessler A, Dauban P, Dodd R, Rognan D, Ruat M. Positive and negative allosteric modulators of the Ca2+-sensing receptor interact within overlapping but not identical binding sites in the transmembrane domain. J Biol Chem. 2004;279:18990-7 pubmed
  46. Tfelt Hansen J, Yano S, John Macleod R, Smajilovic S, Chattopadhyay N, Brown E. High calcium activates the EGF receptor potentially through the calcium-sensing receptor in Leydig cancer cells. Growth Factors. 2005;23:117-23 pubmed
    ..In conclusion, the calcium activates the EGFR, possibly through the CaR, to regulate downstream signaling events and important biological functions in a model of HHM. ..
  47. Kessler A, Faure H, Petrel C, Ruat M, Dauban P, Dodd R. N2-benzyl-N1-(1-(1-naphthyl)ethyl)-3-phenylpropane-1,2-diamines and conformationally restrained indole analogues: development of calindol as a new calcimimetic acting at the calcium sensing receptor. Bioorg Med Chem Lett. 2004;14:3345-9 pubmed
    ..0+/-0.1 or 0.31+/-0.05 microM in cells expressing the rat or the human CaSR, respectively. The calcimimetic activities of these novel compounds were shown to be due to a specific interaction with the CaSR...
  48. Thakker R. Diseases associated with the extracellular calcium-sensing receptor. Cell Calcium. 2004;35:275-82 pubmed
    ..e. autoimmune) of hypoparathyroidism. Thus, abnormalities of the CaSR are associated with three hypercalcaemic and three hypocalcaemic disorders. ..
  49. Vezzoli G, Tanini A, Ferrucci L, Soldati L, Bianchin C, Franceschelli F, et al. Influence of calcium-sensing receptor gene on urinary calcium excretion in stone-forming patients. J Am Soc Nephrol. 2002;13:2517-23 pubmed
    ..Arg990Gly polymorphism could facilitate activation of CaSR and increase Ca excretion and susceptibility to idiopathic hypercalciuria. ..
  50. Rodriguez M, Nemeth E, Martin D. The calcium-sensing receptor: a key factor in the pathogenesis of secondary hyperparathyroidism. Am J Physiol Renal Physiol. 2005;288:F253-64 pubmed
    ..Effective new treatments for SHPT that have a positive impact on mineral metabolism are clearly needed. Recent research shows that drugs that selectively target the CaR, calcimimetics, have the potential to meet these requirements. ..
  51. Pearce S. Clinical disorders of extracellular calcium-sensing and the molecular biology of the calcium-sensing receptor. Ann Med. 2002;34:201-6 pubmed
    ..In the future, therapeutic compounds that modulate calcium-sensing receptor function may have a role in the medical management of hyperparathyroidism (calcimimetic drugs) and osteoporosis (calcilytic drugs). ..
  52. Moe S, Cunningham J, Bommer J, Adler S, Rosansky S, Urena Torres P, et al. Long-term treatment of secondary hyperparathyroidism with the calcimimetic cinacalcet HCl. Nephrol Dial Transplant. 2005;20:2186-93 pubmed
    ..In this long-term study, cinacalcet effectively sustained reductions in PTH for up to 3 years without increasing concentrations of serum calcium, phosphorus or calcium-phosphorus product. ..
  53. Tfelt Hansen J, MacLeod R, Chattopadhyay N, Yano S, Quinn S, Ren X, et al. Calcium-sensing receptor stimulates PTHrP release by pathways dependent on PKC, p38 MAPK, JNK, and ERK1/2 in H-500 cells. Am J Physiol Endocrinol Metab. 2003;285:E329-37 pubmed
    ..We conclude that CaR regulation of PTHrP release in H-500 cells involves activation of PKC as well as the ERK1/2, p38 MAPK, and JNK pathways. ..