“Calcium-sensing receptor”的意思、由来-开放百科全书

The calcium-sensing receptor (CaSR) is a Class C G-protein coupled receptor which senses extracellular levels of calcium ion. It is primarily expressed in the parathyroid gland and the renal tubules of the kidney. In the parathyroid gland, the calcium-sensing receptor controls calcium homeostasis by regulating the release of parathyroid hormone (PTH).^[1] 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.^[2]

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,^[3]^[4] presumably through a G_qα 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^[5] sources state) the cAMP dependent pathway.^[4]

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),^[6] when present in heterozygotes. Patients who are homozygous for CaSR inactivating mutations have more severe hypercalcemia.^[7] Other mutations that activate CaSR are the cause of autosomal dominant hypocalcemia^[8] 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.^[9]

Therapeutic application

The drugs cinacalcet and etelcalcetide are allosteric modifiers of the calcium-sensing receptor.^[10] 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.^[11]^[12] 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,^[13]^[14]^[15]^[15]^[16] 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^[17].

Interactions

References

1. ^{{cite journal | vauthors = D'Souza-Li L | title = The calcium-sensing receptor and related diseases | journal = Arquivos Brasileiros de Endocrinologia e Metabologia | volume = 50 | issue = 4 | pages = 628–39 | date = Aug 2006 | pmid = 17117288 | doi = 10.1590/S0004-27302006000400008 }}
2. ^{{Cite journal|last=Vezzoli|first=Giuseppe|last2=Soldati|first2=Laura|last3=Gambaro|first3=Giovanni|date=2009-04-01|title=Roles of calcium-sensing receptor (CaSR) in renal mineral ion transport|journal=Current Pharmaceutical Biotechnology|volume=10|issue=3|pages=302–310|issn=1873-4316|pmid=19355940|doi=10.2174/138920109787847475}}
3. ^InterPro: IPR000068 GPCR, family 3, extracellular calcium-sensing receptor-related Retrieved on June 2, 2009
4. ^¹{{cite journal | vauthors = Coburn JW, Elangovan L, Goodman WG, Frazaõ JM | title = Calcium-sensing receptor and calcimimetic agents | journal = Kidney International Supplement | volume = 73 | issue = | pages = S52–8 | date = Dec 1999 | pmid = 10633465 | doi = }}
5. ^{{cite book | last = Costanzo | first = Linda S. | title = BRS Physiology (Board Review Series) | authorlink = | year = 2007 | location = | pages = 260 | url = https://www.amazon.com/Physiology-Board-Review-Linda-Costanzo/dp/0781773113/ | doi = | id = | isbn = 978-0-7817-7311-9 }}
6. ^{{cite journal | vauthors = Pidasheva S, Canaff L, Simonds WF, Marx SJ, Hendy GN | title = Impaired cotranslational processing of the calcium-sensing receptor due to signal peptide missense mutations in familial hypocalciuric hypercalcemia | journal = Human Molecular Genetics | volume = 14 | issue = 12 | pages = 1679–90 | date = Jun 2005 | pmid = 15879434 | doi = 10.1093/hmg/ddi176 }}
7. ^{{cite journal | vauthors = Egbuna OI, Brown EM | title = Hypercalcaemic and hypocalcaemic conditions due to calcium-sensing receptor mutations | journal = Best Practice & Research. Clinical Rheumatology | volume = 22 | issue = 1 | pages = 129–148 | date = Mar 2008 | pmid = 18328986 | pmc = 2364635 | doi = 10.1016/j.berh.2007.11.006 }}
8. ^{{cite journal | vauthors = Mancilla EE, De Luca F, Baron J | title = Activating mutations of the Ca2+-sensing receptor | journal = Molecular Genetics and Metabolism | volume = 64 | issue = 3 | pages = 198–204 | date = Jul 1998 | pmid = 9719629 | doi = 10.1006/mgme.1998.2716 }}
9. ^{{cite web | title = Entrez Gene: CaSR calcium-sensing receptor (hypocalciuric hypercalcemia 1, severe neonatal hyperparathyroidism)| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=846| accessdate = }}
10. ^{{cite journal | vauthors = Torres PU | title = Cinacalcet HCl: a novel treatment for secondary hyperparathyroidism caused by chronic kidney disease | journal = Journal of Renal Nutrition | volume = 16 | issue = 3 | pages = 253–8 | date = Jul 2006 | pmid = 16825031 | doi = 10.1053/j.jrn.2006.04.010 }}
11. ^{{cite journal | vauthors = Nemeth EF, Shoback D | title = Calcimimetic and calcilytic drugs for treating bone and mineral-related disorders | journal = Best Practice & Research. Clinical Endocrinology & Metabolism | volume = 27 | issue = 3 | date = Jun 2013 | pmid = 23856266 | doi = 10.1016/j.beem.2013.02.008 | pages=373–84}}
12. ^{{cite journal | vauthors = John MR, Harfst E, Loeffler J, Belleli R, Mason J, Bruin GJ, Seuwen K, Klickstein LB, Mindeholm L, Widler L, Kneissel M | title = AXT914 a novel, orally-active parathyroid hormone-releasing drug in two early studies of healthy volunteers and postmenopausal women | journal = Bone | volume = 64 | date = Jul 2014 | pmid = 24769332 | doi = 10.1016/j.bone.2014.04.015 | pages=204–10}}
13. ^{{cite journal | vauthors = Kim JY, Ho H, Kim N, Liu J, Tu CL, Yenari MA, Chang W | title = Calcium-sensing receptor (CaSR) as a novel target for ischemic neuroprotection | journal = Annals of Clinical and Translational Neurology | volume = 1 | issue = 11 | date = Nov 2014 | pmid = 25540800 | doi = 10.1002/acn3.118 | pages=851–66 | pmc=4265057}}
14. ^{{cite journal | vauthors = Aggarwal A, Prinz-Wohlgenannt M, Tennakoon S, Höbaus J, Boudot C, Mentaverri R, Brown EM, Baumgartner-Parzer S, Kállay E | title = The calcium-sensing receptor: A promising target for prevention of colorectal cancer | journal = Biochimica et Biophysica Acta | date = Feb 2015 | pmid = 25701758 | doi = 10.1016/j.bbamcr.2015.02.011 | volume=1853 | pages=2158–67 | pmc=4549785}}
15. ^¹{{cite journal | vauthors = Dal Prà I, Chiarini A, Armato U | title = Antagonizing amyloid-β/calcium-sensing receptor signaling in human astrocytes and neurons: a key to halt Alzheimer's disease progression? | journal = Neural Regeneration Research | volume = 10 | issue = 2 | date = Feb 2015 | pmid = 25883618 | doi = 10.4103/1673-5374.152373 | pages=213–8 | pmc=4392667}}
16. ^{{cite journal | vauthors = 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 | title = Calcium-sensing receptor antagonists abrogate airway hyperresponsiveness and inflammation in allergic asthma | journal = Science Translational Medicine | volume = 7 | issue = 284 | date = Apr 2015 | pmid = 25904744 | doi = 10.1126/scitranslmed.aaa0282 | pages=284ra60 | pmc=4725057}}
17. ^{{Cite journal|last=Sarem|first=Melika|last2=Heizmann|first2=Miriam|last3=Barbero|first3=Andrea|last4=Martin|first4=Ivan|last5=Shastri|first5=V. Prasad|date=2018-07-03|title=Hyperstimulation of CaSR in human MSCs by biomimetic apatite inhibits endochondral ossification via temporal down-regulation of PTH1R|url=http://www.pnas.org/content/115/27/E6135|journal=Proceedings of the National Academy of Sciences|language=en|volume=115|issue=27|pages=E6135–E6144|doi=10.1073/pnas.1805159115|issn=0027-8424|pmid=29915064}}
18. ^{{cite journal | vauthors = Hjälm G, MacLeod RJ, Kifor O, Chattopadhyay N, Brown EM | title = 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 | journal = The Journal of Biological Chemistry | volume = 276 | issue = 37 | pages = 34880–7 | date = Sep 2001 | pmid = 11390380 | doi = 10.1074/jbc.M100784200 }}
19. ^{{cite journal | vauthors = Awata H, Huang C, Handlogten ME, Miller RT | title = Interaction of the calcium-sensing receptor and filamin, a potential scaffolding protein | journal = The Journal of Biological Chemistry | volume = 276 | issue = 37 | pages = 34871–9 | date = Sep 2001 | pmid = 11390379 | doi = 10.1074/jbc.M100775200 }}

Further reading

{{cite journal | vauthors = Hendy GN, D'Souza-Li L, Yang B, Canaff L, Cole DE | title = Mutations of the calcium-sensing receptor (CASR) in familial hypocalciuric hypercalcemia, neonatal severe hyperparathyroidism, and autosomal dominant hypocalcemia | journal = Human Mutation | volume = 16 | issue = 4 | pages = 281–96 | date = Oct 2000 | pmid = 11013439 | doi = 10.1002/1098-1004(200010)16:4<281::AID-HUMU1>3.0.CO;2-A }}

{{cite journal | vauthors = Fukumoto S | title = [Calcium-sensing receptor in bone cells] | journal = Nihon Rinsho. Japanese Journal of Clinical Medicine | volume = 60 Suppl 3 | issue = | pages = 57–63 | date = Mar 2002 | pmid = 11979955 | doi = }}

{{cite journal | vauthors = Tfelt-Hansen J, Schwarz P, Brown EM, Chattopadhyay N | title = The calcium-sensing receptor in human disease | journal = Frontiers in Bioscience | volume = 8 | issue = | pages = s377–90 | date = May 2003 | pmid = 12700051 | doi = 10.2741/1068 }}

{{cite journal | vauthors = Hu J, Spiegel AM | title = Naturally occurring mutations of the extracellular Ca2+-sensing receptor: implications for its structure and function | journal = Trends in Endocrinology and Metabolism | volume = 14 | issue = 6 | pages = 282–8 | date = Aug 2003 | pmid = 12890593 | doi = 10.1016/S1043-2760(03)00104-8 }}

{{cite journal | vauthors = Aida K, Koishi S, Inoue M, Nakazato M, Tawata M, Onaya T | title = Familial hypocalciuric hypercalcemia associated with mutation in the human Ca(2+)-sensing receptor gene | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 80 | issue = 9 | pages = 2594–8 | date = Sep 1995 | pmid = 7673400 | doi = 10.1210/jc.80.9.2594 }}

{{cite journal | vauthors = Aida K, Koishi S, Tawata M, Onaya T | title = Molecular cloning of a putative Ca(2+)-sensing receptor cDNA from human kidney | journal = Biochemical and Biophysical Research Communications | volume = 214 | issue = 2 | pages = 524–9 | date = Sep 1995 | pmid = 7677761 | doi = 10.1006/bbrc.1995.2318 }}

{{cite journal | vauthors = Chou YH, Pollak MR, Brandi ML, Toss G, Arnqvist H, Atkinson AB, Papapoulos SE, Marx S, Brown EM, Seidman JG | title = Mutations in the human Ca(2+)-sensing-receptor gene that cause familial hypocalciuric hypercalcemia | journal = American Journal of Human Genetics | volume = 56 | issue = 5 | pages = 1075–9 | date = May 1995 | pmid = 7726161 | pmc = 1801464 | doi = }}

{{cite journal | vauthors = Garrett JE, Capuano IV, Hammerland LG, Hung BC, Brown EM, Hebert SC, Nemeth EF, Fuller F | title = Molecular cloning and functional expression of human parathyroid calcium receptor cDNAs | journal = The Journal of Biological Chemistry | volume = 270 | issue = 21 | pages = 12919–25 | date = May 1995 | pmid = 7759551 | doi = 10.1074/jbc.270.21.12919 }}

{{cite journal | vauthors = Pollak MR, Brown EM, Estep HL, McLaine PN, Kifor O, Park J, Hebert SC, Seidman CE, Seidman JG | title = Autosomal dominant hypocalcaemia caused by a Ca(2+)-sensing receptor gene mutation | journal = Nature Genetics | volume = 8 | issue = 3 | pages = 303–7 | date = Nov 1994 | pmid = 7874174 | doi = 10.1038/ng1194-303 }}

{{cite journal | vauthors = Pollak MR, Brown EM, Chou YH, Hebert SC, Marx SJ, Steinmann B, Levi T, Seidman CE, Seidman JG | title = Mutations in the human Ca(2+)-sensing receptor gene cause familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism | journal = Cell | volume = 75 | issue = 7 | pages = 1297–303 | date = Dec 1993 | pmid = 7916660 | doi = 10.1016/0092-8674(93)90617-Y }}

{{cite journal | vauthors = Janicic N, Soliman E, Pausova Z, Seldin MF, Rivière M, Szpirer J, Szpirer C, Hendy GN | title = Mapping of the calcium-sensing receptor gene (CASR) to human chromosome 3q13.3-21 by fluorescence in situ hybridization, and localization to rat chromosome 11 and mouse chromosome 16 | journal = Mammalian Genome | volume = 6 | issue = 11 | pages = 798–801 | date = Nov 1995 | pmid = 8597637 | pmc = | doi = 10.1007/BF00539007 }}

{{cite journal | vauthors = Bikle DD, Ratnam A, Mauro T, Harris J, Pillai S | title = Changes in calcium responsiveness and handling during keratinocyte differentiation. Potential role of the calcium receptor | journal = The Journal of Clinical Investigation | volume = 97 | issue = 4 | pages = 1085–93 | date = Feb 1996 | pmid = 8613532 | pmc = 507156 | doi = 10.1172/JCI118501 }}

{{cite journal | vauthors = Pearce SH, Trump D, Wooding C, Besser GM, Chew SL, Grant DB, Heath DA, Hughes IA, Paterson CR, Whyte MP | title = Calcium-sensing receptor mutations in familial benign hypercalcemia and neonatal hyperparathyroidism | journal = The Journal of Clinical Investigation | volume = 96 | issue = 6 | pages = 2683–92 | date = Dec 1995 | pmid = 8675635 | pmc = 185975 | doi = 10.1172/JCI118335 }}

{{cite journal | vauthors = Bai M, Quinn S, Trivedi S, Kifor O, Pearce SH, Pollak MR, Krapcho K, Hebert SC, Brown EM | title = Expression and characterization of inactivating and activating mutations in the human Ca2+o-sensing receptor | journal = The Journal of Biological Chemistry | volume = 271 | issue = 32 | pages = 19537–45 | date = Aug 1996 | pmid = 8702647 | doi = 10.1074/jbc.271.32.19537 }}

{{cite journal | vauthors = Baron J, Winer KK, Yanovski JA, Cunningham AW, Laue L, Zimmerman D, Cutler GB | title = Mutations in the Ca(2+)-sensing receptor gene cause autosomal dominant and sporadic hypoparathyroidism | journal = Human Molecular Genetics | volume = 5 | issue = 5 | pages = 601–6 | date = May 1996 | pmid = 8733126 | doi = 10.1093/hmg/5.5.601 }}

{{cite journal | vauthors = Freichel M, Zink-Lorenz A, Holloschi A, Hafner M, Flockerzi V, Raue F | title = Expression of a calcium-sensing receptor in a human medullary thyroid carcinoma cell line and its contribution to calcitonin secretion | journal = Endocrinology | volume = 137 | issue = 9 | pages = 3842–8 | date = Sep 1996 | pmid = 8756555 | doi = 10.1210/en.137.9.3842 }}

{{cite journal | vauthors = Chattopadhyay N, Ye C, Singh DP, Kifor O, Vassilev PM, Shinohara T, Chylack LT, Brown EM | title = Expression of extracellular calcium-sensing receptor by human lens epithelial cells | journal = Biochemical and Biophysical Research Communications | volume = 233 | issue = 3 | pages = 801–5 | date = Apr 1997 | pmid = 9168937 | doi = 10.1006/bbrc.1997.6553 }}

{{cite journal | vauthors = Cole DE, Janicic N, Salisbury SR, Hendy GN | title = Neonatal severe hyperparathyroidism, secondary hyperparathyroidism, and familial hypocalciuric hypercalcemia: multiple different phenotypes associated with an inactivating Alu insertion mutation of the calcium-sensing receptor gene | journal = American Journal of Medical Genetics | volume = 71 | issue = 2 | pages = 202–10 | date = Aug 1997 | pmid = 9217223 | doi = 10.1002/(SICI)1096-8628(19970808)71:2<202::AID-AJMG16>3.0.CO;2-I }}

{{cite journal | vauthors = Ward BK, Stuckey BG, Gutteridge DH, Laing NG, Pullan PT, Ratajczak T | title = A novel mutation (L174R) in the Ca2+-sensing receptor gene associated with familial hypocalciuric hypercalcemia | journal = Human Mutation | volume = 10 | issue = 3 | pages = 233–5 | year = 1997 | pmid = 9298824 | doi = 10.1002/(SICI)1098-1004(1997)10:3<233::AID-HUMU9>3.0.CO;2-J }}

{{cite journal | vauthors = Quinn SJ, Kifor O, Trivedi S, Diaz R, Vassilev P, Brown E | title = Sodium and ionic strength sensing by the calcium receptor | journal = The Journal of Biological Chemistry | volume = 273 | issue = 31 | pages = 19579–86 | date = Jul 1998 | pmid = 9677383 | doi = 10.1074/jbc.273.31.19579 }}

{{cite journal | vauthors = Magno AL, Ward BK, Ratajczak T | title = The calcium-sensing receptor: a molecular perspective | journal = Endocrine Reviews | volume = 32 | issue = 1 | pages = 3–30 | date = Feb 2011 | pmid = 20729338 | doi = 10.1210/er.2009-0043 }}

External links

{{cite web | url = http://www.iuphar-db.org/GPCR/ChapterMenuForward?chapterID=1322 | title = Calcium-Sensing Receptors | accessdate = | author = | authorlink = | format = | work = IUPHAR Database of Receptors and Ion Channels | publisher = International Union of Basic and Clinical Pharmacology | pages = | archiveurl = | archivedate = | quote = }}

CASRdb - Calcium Sensing Receptor Database, McGill University

1 : G protein-coupled receptors