More information on this family may be found on the IUPHAR-DB family and introduction pages.
The calcium-sensing receptor (CaS, provisional nomenclature) responds to extracellular calcium and magnesium in the millimolar range and to gadolinium and some polycations in the micromolar range [1]. The sensitivity of CaS to primary agonists can be increased by aromatic L-amino acids [3] and also by elevated extracellular pH [13] or decreased extracellular ionic strength [14].
Unless otherwise stated all data refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).
Receptors 
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Brown, EM. (2007) Clinical lessons from the calcium-sensing receptor. Nat Clin Pract Endocrinol Metab, 3 (2): 122-33. [PMID:17237839]
Cavanaugh, A; Huang, Y; Breitwieser, GE. (2011) Behind the curtain: Cellular mechanisms for allosteric modulation of calcium sensing receptors. Br J Pharmacol, [Epub ahead of print]. [PMID:21470201]
Khan, MA; Conigrave, AD. (2010) Mechanisms of multimodal sensing by extracellular Ca(2+)-sensing receptors: a domain-based survey of requirements for binding and signalling. Br. J. Pharmacol., 159 (5): 1039-50. [PMID:20136834]
Magno, AL; Ward, BK; Ratajczak, T. (2011) The calcium-sensing receptor: a molecular perspective. Endocr. Rev., 32 (1): 3-30. [PMID:20729338]
Ward, DT; Riccardi, D. (2011) NEW CONCEPTS IN CALCIUM-SENSING RECEPTOR PHARMACOLOGY AND SIGNALLING. Br J Pharmacol, [Epub ahead of print]. [PMID:21627634]
1. Brown, E. M., Gamba, G., Riccardi, D., Lombardi, D., Butters, R., Kifor, O., Sun, A., Hediger, M. A., Lytton, J. and Hebert, S. C. (1993) Cloning and characterization of an extracellular Ca2+-sensing receptor from bovine parathyroid. Nature, 366: 575-580. [PMID:8255296]
2. Chang, W; Tu, C; Chen, TH; Bikle, D; Shoback, D. (2008) The extracellular calcium-sensing receptor (CaSR) is a critical modulator of skeletal development. Sci Signal, 1 (35): ra1. [PMID:18765830]
3. Conigrave, A. D., Quinn, S. J. and Brown, E. M. (2000) Calcium-dependent activation of the Ca2+sensing receptor by aromatic amino acids. Proc Natl Acad Sci USA , 97: 4814-4819. [PMID:10781086]
4. Ho, C., Conner, D. A., Pollak, M. R., Ladd, D. J., Kifor, O., Warren, H. B., Brown, E. M., Seidman, J. G. and Seidman, C. E. (1995) A mouse model of human familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Nat Genet., 11: 389-394. [PMID:7493018]
5. Kessler, A., Faure, H., Petrel, C., Ruat, M., Dauban, P. and Dodd, R. H. (2004) N(2)-benzyl-N(1)-(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., 14: 3345-3349. [PMID:15149704]
6. Ma, JN; Owens, M; Gustafsson, M; Jensen, J; Tabatabaei, A; Schmelzer, K; Olsson, R; Burstein, ES. (2011) Characterization of highly efficacious allosteric agonists of the human calcium-sensing receptor. J. Pharmacol. Exp. Ther., 337 (1): 275-84. [PMID:21239511]
7. Nemeth, E. F., Delmar, E. G., Heaton, W. L., Miller, M. A., Lambert, L. D., Conklin, R. L., Gowen, M., Gleason, J. G., Bhatnagar, P. K. and Fox, J. (2001) Calcilytic compounds: potent and selective Ca2+ receptor antagonists that stimulate secretion of parathyroid hormone. J Pharmacol Exp Ther., 299: 323-331. [PMID:11561095]
8. Nemeth, E. F., Steffey, M. E., Hammerland, L. G., Hung, B. C., Van Wagenen, B. C., Delmar, E. G. and Balandrin, M. F. (1998) Calcimimetics with potent and selective activity on the parathyroid calcium receptor. Proc Natl Acad Sci U S A., 95: 4040-4045. [PMID:9520489]
9. Nemeth, EF; Heaton, WH; Miller, M; Fox, J; Balandrin, MF; Van Wagenen, BC; Colloton, M; Karbon, W; Scherrer, J; Shatzen, E; et al.. (2004) Pharmacodynamics of the type II calcimimetic compound cinacalcet HCl. J. Pharmacol. Exp. Ther., 308 (2): 627-35. [PMID:14593085]
10. Petrel, C., Kessler, A., Maslah, F., Dauban, P., Dodd, R. H., Rognan, D. and Ruat, M. (2003) Modeling and mutagenesis of the binding site of Calhex 231, a novel negative allosteric modulator of the extracellular Ca(2+)-sensing receptor. J Biol Chem., 278: 49487-49494. [PMID:14506236]
11. Petrel, C; Kessler, A; Dauban, P; Dodd, RH; Rognan, D; Ruat, M. (2004) 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., 279 (18): 18990-7. [PMID:14976203]
12. Quinn, S. J., Ye, C. P., Diaz, R., Kifor, O., Bai, M., Vassilev, P. and Brown, E. M. (1997) The calcium-sensing receptor: a target for polyamines. Am J Physiol, 273: C1315-C1323. [PMID:9357776]
13. Quinn, SJ; Bai, M; Brown, EM. (2004) pH Sensing by the calcium-sensing receptor. J. Biol. Chem., 279 (36): 37241-9. [PMID:15201280]
14. Quinn, SJ; Kifor, O; Trivedi, S; Diaz, R; Vassilev, P; Brown, E. (1998) Sodium and ionic strength sensing by the calcium receptor. J. Biol. Chem., 273 (31): 19579-86. [PMID:9677383]
15. Ward, DT. (2004) Calcium receptor-mediated intracellular signalling. Cell Calcium, 35 (3): 217-28. [PMID:15200145]
16. Wellendorph, P., Hansen, K. B., Balsgaard, A., Greenwood, J. R., Egebjerg, J. and Brauner-Osborne, H. (2005) Deorphanization of GPRC6A: a promiscuous L-alpha-amino acid receptor with preference for basic amino acids. Mol Pharmacol., 67: 589-597. [PMID:15576628]
17. Yang, W., Wang, Y., Roberge, J. Y., Ma, Z., Liu, Y., Michael Lawrence, R., Rotella, D. P., Seethala, R., Feyen, J. H. and Dickson, J. K. (2005) Discovery and structure-activity relationships of 2-benzylpyrrolidine-substituted aryloxypropanols as calcium-sensing receptor antagonists. Bioorg Med Chem Lett, 15: 1225-1228. [PMID:15686947]
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Positive allosteric modulators are termed Type II calcimimetics and can suppress parathyroid hormone (PTH) secretion [8]. Negative allosteric modulators are called calcilytics and can act to increase PTH secretion [7].
The central role of CaS in the maintenance of extracellular calcium homeostasis is seen most clearly in patients with loss-of-function CaS mutations who develop familial hypocalciuric hypercalcaemia (heterozygous mutation) or neonatal severe hyperparathyroidism (homozygous mutation) and in CaS null mice [2,4], which exhibit similar increases in PTH secretion and blood Ca2+ levels. A gain-of-function mutation in the CaS gene is associated with autosomal dominant hypocalcaemia.