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Calcium-sensing receptor

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CASR
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesCASR, CAR, EIG8, FHH, FIH, GPRC2A, HHC, HHC1, HYPOC1, NSHPT, PCAR1, calcium sensing receptor, hCasR, Calcium-sensing receptor+CaSR
External IDsOMIM: 601199; MGI: 1351351; HomoloGene: 332; GeneCards: CASR; OMA:CASR - orthologs
Orthologs
SpeciesHumanMouse
Entrez

846

12374

Ensembl

ENSG00000036828

ENSMUSG00000051980

UniProt

P41180

Q9QY96

RefSeq (mRNA)

NM_000388
NM_001178065

NM_013803

RefSeq (protein)

NP_000379
NP_001171536

NP_038831

Location (UCSC)Chr 3: 122.18 – 122.29 MbChr 16: 36.31 – 36.38 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

The calcium-sensing receptor (CaSR) is a Class C G-protein coupled receptor which senses extracellular levels of calcium ions. It is primarily expressed in the parathyroid gland, the renal tubules of the kidney and the brain.[5][6] In the parathyroid gland, it controls calcium homeostasis by regulating the release of parathyroid hormone (PTH).[7] In the kidney it has an inhibitory effect on the reabsorption of calcium, potassium, sodium, and water depending on which segment of the tubule is being activated.[8]

Since the initial review of CaSR,[9] there has been in-depth analysis of its role related to parathyroid disease and other roles related to tissues and organs in the body. 1993, Brown et al.[10] isolated a clone named BoPCaR (bovine parathyroid calcium receptor) which replicated the effect when introduced to polyvalent cations. Because of this, the ability to clone full-length CaSRs from mammals were performed.[11]

Signal transduction

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,[12][13] presumably through a Gqα 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[14] sources state) the cAMP dependent pathway.[13]

Pathology

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),[15] when present in heterozygotes. Patients who are homozygous for CaSR inactivating mutations have more severe hypercalcemia.[16] Other mutations that activate CaSR are the cause of autosomal dominant hypocalcemia[17] 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.[18]

Therapeutic application

The drugs cinacalcet and etelcalcetide are allosteric modifiers of the calcium-sensing receptor.[19] They are classified as a calcimimetics, binding to the calcium-sensing receptor and decreasing 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.[20][21] 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,[22][23][24][25] and calcilytic drugs are being researched as potential treatments for these. Recently it has been shown that biomimetic bone like apatite inhibits formation of bone through endochondral ossification pathway via hyperstimulation of extracellular calcium sensing receptor.[26]

Interactions

Calcium-sensing receptor has been shown to interact with filamin.[27][28]

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000036828 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000051980 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Yano S, Brown EM, Chattopadhyay N (March 2004). "Calcium-sensing receptor in the brain". Cell Calcium. 35 (3): 257–64. doi:10.1016/j.ceca.2003.10.008. PMID 15200149.
  6. ^ Giudice ML, Mihalik B, Dinnyés A, Kobolák J (July 2019). "The Nervous System Relevance of the Calcium Sensing Receptor in Health and Disease". Molecules. 24 (14): 2546. doi:10.3390/molecules24142546. PMC 6680999. PMID 31336912.
  7. ^ D'Souza-Li L (August 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.
  8. ^ Vezzoli G, Soldati L, Gambaro G (April 2009). "Roles of calcium-sensing receptor (CaSR) in renal mineral ion transport". Current Pharmaceutical Biotechnology. 10 (3): 302–10. doi:10.2174/138920109787847475. PMID 19355940.
  9. ^ Brown, E. M.; Pollak, M.; Riccardi, D.; Hebert, S. C. (1994). "Cloning and characterization of an extracellular Ca(2+)-sensing receptor from parathyroid and kidney: new insights into the physiology and pathophysiology of calcium metabolism". Nephrology, Dialysis, Transplantation. 9 (12): 1703–1706. ISSN 0931-0509. PMID 7708247.
  10. ^ "Cloning and characterization of an extracellular Ca2+ -sensing receptor from parathyroid and kidney: new insights into the physiology and pathophysiology of calcium metabolism". Nephrology Dialysis Transplantation. 1994. doi:10.1093/ndt/9.12.1703. ISSN 1460-2385.
  11. ^ Aida, K.; Koishi, S.; Tawata, M.; Onaya, T. (September 1995). "Molecular Cloning of a Putative Ca2+-Sensing Receptor cDNA from Human Kidney". Biochemical and Biophysical Research Communications. 214 (2): 524–529. doi:10.1006/bbrc.1995.2318. ISSN 0006-291X. PMID 7677761.
  12. ^ InterPro: IPR000068 GPCR, family 3, extracellular calcium-sensing receptor-related Retrieved on June 2, 2009
  13. ^ a b Coburn JW, Elangovan L, Goodman WG, Frazaõ JM (Dec 1999). "Calcium-sensing receptor and calcimimetic agents". Kidney International Supplements. 73: S52–8. doi:10.1046/j.1523-1755.1999.07303.x. PMID 10633465.
  14. ^ Costanzo LS (2007). BRS Physiology (Board Review Series). Lippincott Williams & Wilkins. pp. 260. ISBN 978-0-7817-7311-9.
  15. ^ Pidasheva S, Canaff L, Simonds WF, Marx SJ, Hendy GN (Jun 2005). "Impaired cotranslational processing of the calcium-sensing receptor due to signal peptide missense mutations in familial hypocalciuric hypercalcemia". Human Molecular Genetics. 14 (12): 1679–90. doi:10.1093/hmg/ddi176. PMID 15879434.
  16. ^ Egbuna OI, Brown EM (Mar 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.
  17. ^ Mancilla EE, De Luca F, Baron J (Jul 1998). "Activating mutations of the Ca2+-sensing receptor". Molecular Genetics and Metabolism. 64 (3): 198–204. doi:10.1006/mgme.1998.2716. PMID 9719629.
  18. ^ "Entrez Gene: CaSR calcium-sensing receptor (hypocalciuric hypercalcemia 1, severe neonatal hyperparathyroidism)".
  19. ^ Torres PU (Jul 2006). "Cinacalcet HCl: a novel treatment for secondary hyperparathyroidism caused by chronic kidney disease". Journal of Renal Nutrition. 16 (3): 253–8. doi:10.1053/j.jrn.2006.04.010. PMID 16825031.
  20. ^ Nemeth EF, Shoback D (Jun 2013). "Calcimimetic and calcilytic drugs for treating bone and mineral-related disorders". Best Practice & Research. Clinical Endocrinology & Metabolism. 27 (3): 373–84. doi:10.1016/j.beem.2013.02.008. PMID 23856266.
  21. ^ John MR, Harfst E, Loeffler J, Belleli R, Mason J, Bruin GJ, Seuwen K, Klickstein LB, Mindeholm L, Widler L, Kneissel M (Jul 2014). "AXT914 a novel, orally-active parathyroid hormone-releasing drug in two early studies of healthy volunteers and postmenopausal women". Bone. 64: 204–10. doi:10.1016/j.bone.2014.04.015. PMID 24769332.
  22. ^ Kim JY, Ho H, Kim N, Liu J, Tu CL, Yenari MA, Chang W (Nov 2014). "Calcium-sensing receptor (CaSR) as a novel target for ischemic neuroprotection". Annals of Clinical and Translational Neurology. 1 (11): 851–66. doi:10.1002/acn3.118. PMC 4265057. PMID 25540800.
  23. ^ Aggarwal A, Prinz-Wohlgenannt M, Tennakoon S, Höbaus J, Boudot C, Mentaverri R, Brown EM, Baumgartner-Parzer S, Kállay E (Feb 2015). "The calcium-sensing receptor: A promising target for prevention of colorectal cancer". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 1853 (9): 2158–67. doi:10.1016/j.bbamcr.2015.02.011. PMC 4549785. PMID 25701758.
  24. ^ Dal Prà I, Chiarini A, Armato U (Feb 2015). "Antagonizing amyloid-β/calcium-sensing receptor signaling in human astrocytes and neurons: a key to halt Alzheimer's disease progression?". Neural Regeneration Research. 10 (2): 213–8. doi:10.4103/1673-5374.152373. PMC 4392667. PMID 25883618.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  25. ^ Yarova PL, Stewart AL, Sathish V, Britt RD, Thompson MA, P Lowe AP, Freeman M, Aravamudan B, Kita H, Brennan SC, Schepelmann M, Davies T, Yung S, Cholisoh Z, Kidd EJ, Ford WR, Broadley KJ, Rietdorf K, Chang W, Bin Khayat ME, Ward DT, Corrigan CJ, T Ward JP, Kemp PJ, Pabelick CM, Prakash YS, Riccardi D (Apr 2015). "Calcium-sensing receptor antagonists abrogate airway hyperresponsiveness and inflammation in allergic asthma". Science Translational Medicine. 7 (284): 284ra60. doi:10.1126/scitranslmed.aaa0282. PMC 4725057. PMID 25904744.
  26. ^ Sarem M, Heizmann M, Barbero A, Martin I, Shastri VP (July 2018). "Hyperstimulation of CaSR in human MSCs by biomimetic apatite inhibits endochondral ossification via temporal down-regulation of PTH1R". Proceedings of the National Academy of Sciences of the United States of America. 115 (27): E6135–E6144. doi:10.1073/pnas.1805159115. PMC 6142224. PMID 29915064.
  27. ^ 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". The Journal of Biological Chemistry. 276 (37): 34880–7. doi:10.1074/jbc.M100784200. PMID 11390380.
  28. ^ Awata H, Huang C, Handlogten ME, Miller RT (Sep 2001). "Interaction of the calcium-sensing receptor and filamin, a potential scaffolding protein". The Journal of Biological Chemistry. 276 (37): 34871–9. doi:10.1074/jbc.M100775200. PMID 11390379.

Further reading

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