Calcium-sensing receptor

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Calcium-sensing receptor
Identifiers
Symbols CASR ; CAR; EIG8; FHH; FIH; GPRC2A; HHC; HHC1; HYPOC1; NSHPT; PCAR1
External IDs OMIM601199 MGI1351351 HomoloGene332 IUPHAR: 54 ChEMBL: 1878 GeneCards: CASR Gene
RNA expression pattern
PBB GE CASR 210577 at tn.png
PBB GE CASR 211384 s at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 846 12374
Ensembl ENSG00000036828 ENSMUSG00000051980
UniProt P41180 Q9QY96
RefSeq (mRNA) NM_000388 NM_013803
RefSeq (protein) NP_000379 NP_038831
Location (UCSC) Chr 3:
121.9 – 122.01 Mb
Chr 16:
36.49 – 36.56 Mb
PubMed search [1] [2]

The calcium-sensing receptor (CaSR) is a Class C G-protein coupled receptor which senses extracellular levels of calcium ion. In the parathyroid gland, the calcium-sensing receptor controls calcium homeostasis by regulating the release of parathyroid hormone (PTH).[1]

Signal transduction[edit]

The release of PTH is inhibited in response to elevations in plasma calcium concentrations and activation of the calcium receptor. Increased calcium binding on the extracellular side gives a conformational change in the receptor, which, on the intracellular side, initiates the phospholipase C pathway,[2][3] presumably through a G type of G protein, which ultimately increases intracellular concentration of calcium, which inhibits vesicle fusion and exocytosis of parathyroid hormone. It also inhibits (not stimulates, as some[4] sources state) the cAMP dependent pathway.[3]

Pathology[edit]

Mutations that inactivate a CaSR gene cause familial hypocalciuric hypercalcemia (FHH) (also known as familial benign hypercalcemia because it is generally asymptomatic and does not require treatment),[5] when present in heterozygotes. Patients who are homozygous for CaSR inactivating mutations have more severe hypercalcemia.[6] Other mutations that activate CaSR are the cause of autosomal dominant hypocalcemia[7] or Type 5 Bartter syndrome. An alternatively spliced transcript variant encoding 1088 aa has been found for this gene, but its full-length nature has not been defined.[8]

Therapeutic application[edit]

The drug cinacalcet is an allosteric modifier of the calcium-sensing receptor.[9] It is classified as a calcimimetic, which binds to the calcium-sensing receptor and decreases parathyroid hormone release.

Calcilytic drugs which block CaSR, produce increased bone density in animal studies and have been researched for the treatment of osteoporosis. Unfortunately clinical trial results in humans have proved disappointing, with sustained changes in bone density not observed despite the drug being well tolerated.[10][11] More recent research has shown the CaSR receptor to be involved in numerous other conditions including Alzheimer's disease, asthma and some forms of cancer,[12][13][14][15] and calcilytic drugs are being researched as potential treatments for these.

Interactions[edit]

Calcium-sensing receptor has been shown to interact with Filamin.[16][17]

References[edit]

  1. ^ D'Souza-Li L (2006). "The calcium-sensing receptor and related diseases". Arquivos brasileiros de endocrinologia e metabologia 50 (4): 628–39. doi:10.1590/S0004-27302006000400008. PMID 17117288. 
  2. ^ InterPro: IPR000068 GPCR, family 3, extracellular calcium-sensing receptor-related Retrieved on June 2, 2009
  3. ^ a b Coburn JW, Elangovan L, Goodman WG, Frazaõ JM (December 1999). "Calcium-sensing receptor and calcimimetic agents". Kidney Int. Suppl. 73: S52–8. PMID 10633465. 
  4. ^ Costanzo, Linda S. (2007). BRS Physiology (Board Review Series). p. 260. ISBN 978-0-7817-7311-9. 
  5. ^ Pidasheva S, Canaff L, Simonds WF, Marx SJ, Hendy GN (2005). "Impaired cotranslational processing of the calcium-sensing receptor due to signal peptide missense mutations in familial hypocalciuric hypercalcemia". Hum. Mol. Genet. 14 (12): 1679–90. doi:10.1093/hmg/ddi176. PMID 15879434. 
  6. ^ Egbuna OI, Brown EM (2008). "Hypercalcaemic and hypocalcaemic conditions due to calcium-sensing receptor mutations". Best Practice & Research Clinical Rheumatology 22 (1): 129–148. doi:10.1016/j.berh.2007.11.006. PMC 2364635. PMID 18328986. 
  7. ^ Mancilla EE, De Luca F, Baron J (1998). "Activating mutations of the Ca2+-sensing receptor". Mol. Genet. Metab. 64 (3): 198–204. doi:10.1006/mgme.1998.2716. PMID 9719629. 
  8. ^ "Entrez Gene: CaSR calcium-sensing receptor (hypocalciuric hypercalcemia 1, severe neonatal hyperparathyroidism)". 
  9. ^ Torres PU (2006). "Cinacalcet HCl: a novel treatment for secondary hyperparathyroidism caused by chronic kidney disease". Journal of renal nutrition : the official journal of the Council on Renal Nutrition of the National Kidney Foundation 16 (3): 253–8. doi:10.1053/j.jrn.2006.04.010. PMID 16825031. 
  10. ^ Nemeth EF, Shoback D. Calcimimetic and calcilytic drugs for treating bone and mineral-related disorders. Best Pract Res Clin Endocrinol Metab. 2013 Jun;27(3):373-84. doi: 10.1016/j.beem.2013.02.008 PMID 23856266
  11. ^ John MR, Harfst E, Loeffler J, Belleli R, Mason J, Bruin GJ, Seuwen K, Klickstein LB, Mindeholm L, Widler L, Kneissel M. AXT914 a novel, orally-active parathyroid hormone-releasing drug in two early studies of healthy volunteers and postmenopausal women. Bone. 2014 Jul;64:204-10. doi: 10.1016/j.bone.2014.04.015 PMID 24769332
  12. ^ Kim JY, Ho H, Kim N, Liu J, Tu CL, Yenari MA, Chang W. Calcium-sensing receptor (CaSR) as a novel target for ischemic neuroprotection. Ann Clin Transl Neurol. 2014 Nov;1(11):851-66. doi: 10.1002/acn3.118 PMID 25540800
  13. ^ Aggarwal A, Prinz-Wohlgenannt M, Tennakoon S, Höbaus J, Boudot C, Mentaverri R, Brown EM, Baumgartner-Parzer S, Kállay E. The calcium-sensing receptor: A promising target for prevention of colorectal cancer. Biochim Biophys Acta. 2015 Feb 18. pii: S0167-4889(15)00051-8. doi: 10.1016/j.bbamcr.2015.02.011 PMID 25701758
  14. ^ Dal Prà I, Chiarini A, Armato U. Antagonizing amyloid-β/calcium-sensing receptor signaling in human astrocytes and neurons: a key to halt Alzheimer's disease progression? Neural Regen Res. 2015 Feb;10(2):213-8. doi: 10.4103/1673-5374.152373 PMID 25883618
  15. ^ Yarova PF, et al. Calcium-sensing receptor antagonists abrogate airway hyperresponsiveness and inflammation in allergic asthma. Science Translational Medicine 22 April 2015;7(284):284ra60 doi: 10.1126/scitranslmed.aaa0282
  16. ^ Hjälm G, MacLeod RJ, Kifor O, Chattopadhyay N, Brown EM (Sep 2001). "Filamin-A binds to the carboxyl-terminal tail of the calcium-sensing receptor, an interaction that participates in CaR-mediated activation of mitogen-activated protein kinase". J. Biol. Chem. (United States) 276 (37): 34880–7. doi:10.1074/jbc.M100784200. ISSN 0021-9258. PMID 11390380. 
  17. ^ Awata H, Huang C, Handlogten ME, Miller RT (Sep 2001). "Interaction of the calcium-sensing receptor and filamin, a potential scaffolding protein". J. Biol. Chem. (United States) 276 (37): 34871–9. doi:10.1074/jbc.M100775200. ISSN 0021-9258. PMID 11390379. 

Further reading[edit]

External links[edit]