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Gene and Protein Information | ||||||
Species | TM | AA | Chromosomal Location | Gene Symbol | Gene Name | Reference |
Human | 4 | 301 | 12q24.31 | ORAI1 | ORAI calcium release-activated calcium modulator 1 | |
Mouse | 4 | 304 | 5 F | Orai1 | ORAI calcium release-activated calcium modulator 1 | |
Rat | 4 | 304 | 12q16 | Orai1 | ORAI calcium release-activated calcium modulator 1 |
Database Links | |
Alphafold | Q96D31 (Hs), Q8BWG9 (Mm), Q5M848 (Rn) |
ChEMBL Target | CHEMBL2384891 (Hs), CHEMBL4295887 (Mm), CHEMBL3721308 (Rn) |
Ensembl Gene | ENSG00000276045 (Hs), ENSMUSG00000049686 (Mm), ENSRNOG00000001336 (Rn) |
Entrez Gene | 84876 (Hs), 109305 (Mm), 304496 (Rn) |
Human Protein Atlas | ENSG00000276045 (Hs) |
KEGG Gene | hsa:84876 (Hs), mmu:109305 (Mm), rno:304496 (Rn) |
OMIM | 610277 |
Orphanet | ORPHA201295 (Hs) |
Pharos | Q96D31 (Hs) |
RefSeq Nucleotide | NM_032790 (Hs), NM_175423 (Mm), NM_001013982 (Rn) |
RefSeq Protein | NP_116179 (Hs), NP_780632 (Mm), NP_001014004 (Rn) |
UniProtKB | Q96D31 (Hs), Q8BWG9 (Mm), Q5M848 (Rn) |
Wikipedia | ORAI1 (Hs) |
Download all structure-activity data for this target as a CSV file
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Immunopharmacology Comments |
ORAI1 is the gene that encodes the essential pore-forming subunit of CRAC store-operated Ca2+ entry (SOCE) channels [20]. It was originally identified in leukemic mast cells [9] and Jurkat T cells [13,30]. ORAI1 is ubiquitously expressed and is essential for the function of T cells, mast cells, and other immune cells [6-7]. CRAC channels are activated by depletion of Ca2+ stores in the endoplasmic reticulum (ER) [30] that results from antigen-induced activation of a range of immunoreceptors (including TCRs, BCRs, Fcγ and Fcε receptors, chemokine GPCRs and some innate pattern-recognition receptors). CRAC channels are gated by stromal interaction molecule (STIM) 1 which is located in the ER, and acts as a sensor of the ER luminal Ca2+ concentration [8,15,17,21-22,28]. The pathophysiological effect of functional CRAC channel deficiency (a CRAC channelopathy) can be caused by loss-of-function mutations in ORAI1 or STIM molecules. Such CRAC channelopathies are characterised by impaired immune cell function and have been identified as an underlying cause of primary immunodeficiency with predominant features that resemble severe combined immunodeficiency disease (SCID), and symptoms that include autoimmunity, muscular hypotonia, and ectodermal dysplasia [3-4,6,16,24]. In addition, selective CRAC channel inhibitors offer the potential for the development of novel safe and potent immune suppressors that woud be applicable to the treatment of autoimmunity and allergy (and cancer) [1-2,23]. The CRAC channel inhibitor CM4620 (CalciMedica; structure likely claimed in patent WO2016138472A1 [27]) is being developed for the treatment of the dynamic inflammatory disease, acute pancreatitis (Phase 2 NCT03401190). CM4620 was granted EMA orphan designation for acute pancreatitis (2016) and was awarded FDA Fast Track designation in 2017. CalciMedica also had an oral CRAC inhibitor, CM2489 in early stage proof-of-concept clinical trial for psoriasis but we can find no current details of any ongoing clinical development (August 2018) [25]. Daiichi Sankyo have developed a humanized anti-ORAI1 monoclonal antibody that inhibits CRAC channel function and inhibits release of IL-2 from human PBMCs, but this has not yet advanced to clinical evaluation [11] |
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1. Chang WC. (2006) Store-operated calcium channels and pro-inflammatory signals. Acta Pharmacol Sin, 27 (7): 813-20. [PMID:16787563]
2. Di Capite JL, Bates GJ, Parekh AB. (2011) Mast cell CRAC channel as a novel therapeutic target in allergy. Curr Opin Allergy Clin Immunol, 11 (1): 33-8. [PMID:21150433]
3. Feske S. (2011) Immunodeficiency due to defects in store-operated calcium entry. Ann N Y Acad Sci, 1238: 74-90. [PMID:22129055]
4. Feske S, Gwack Y, Prakriya M, Srikanth S, Puppel SH, Tanasa B, Hogan PG, Lewis RS, Daly M, Rao A. (2006) A mutation in Orai1 causes immune deficiency by abrogating CRAC channel function. Nature, 441 (7090): 179-85. [PMID:16582901]
5. Feske S, Müller JM, Graf D, Kroczek RA, Dräger R, Niemeyer C, Baeuerle PA, Peter HH, Schlesier M. (1996) Severe combined immunodeficiency due to defective binding of the nuclear factor of activated T cells in T lymphocytes of two male siblings. Eur J Immunol, 26 (9): 2119-26. [PMID:8814256]
6. Feske S, Wulff H, Skolnik EY. (2015) Ion channels in innate and adaptive immunity. Annu Rev Immunol, 33: 291-353. [PMID:25861976]
7. Gwack Y, Srikanth S, Feske S, Cruz-Guilloty F, Oh-hora M, Neems DS, Hogan PG, Rao A. (2007) Biochemical and functional characterization of Orai proteins. J Biol Chem, 282 (22): 16232-43. [PMID:17293345]
8. Hogan PG, Lewis RS, Rao A. (2010) Molecular basis of calcium signaling in lymphocytes: STIM and ORAI. Annu Rev Immunol, 28: 491-533. [PMID:20307213]
9. Hoth M, Penner R. (1992) Depletion of intracellular calcium stores activates a calcium current in mast cells. Nature, 355 (6358): 353-6. [PMID:1309940]
10. Khedkar NR, Irlapatti NR, Dadke D, Kanoje V, Shaikh Z, Karche V, Shinde V, Deshmukh G, Patil A, Jachak S et al.. (2021) Discovery of a Novel Potent and Selective Calcium Release-Activated Calcium Channel Inhibitor: 2,6-Difluoro-N-(2'-methyl-3'-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-[1,1'-biphenyl]-4-yl)benzamide. Structure-Activity Relationship and Preclinical Characterization. J Med Chem, 64 (23): 17004-17030. [PMID:34843241]
11. Komai T, Kimura T, Baba D, Onodera Y, Tanaka K, Kagari T, Aki A, Nagaoka N. (2017) Anti-Orai1 Antibody. Patent number: US20170226203A1. Assignee: Daiichi Sankyo Co Ltd. Priority date: 07/08/2014. Publication date: 10/08/2017.
12. Le Deist F, Hivroz C, Partiseti M, Thomas C, Buc HA, Oleastro M, Belohradsky B, Choquet D, Fischer A. (1995) A primary T-cell immunodeficiency associated with defective transmembrane calcium influx. Blood, 85 (4): 1053-62. [PMID:7531512]
13. Lewis RS, Cahalan MD. (1989) Mitogen-induced oscillations of cytosolic Ca2+ and transmembrane Ca2+ current in human leukemic T cells. Cell Regul, 1 (1): 99-112. [PMID:2519622]
14. Liardo E, Pham AT, Ghilardi AF, Zhelay T, Szteyn K, Gandi NL, Ekkati A, Koerner S, Kozak JA, Sun L. (2024) Discovery of selective Orai channel blockers bearing an indazole or a pyrazole scaffold. Eur J Med Chem, 278: 116805. [PMID:39232360]
15. Liou J, Kim ML, Heo WD, Jones JT, Myers JW, Ferrell Jr JE, Meyer T. (2005) STIM is a Ca2+ sensor essential for Ca2+-store-depletion-triggered Ca2+ influx. Curr Biol, 15 (13): 1235-41. [PMID:16005298]
16. McCarl CA, Picard C, Khalil S, Kawasaki T, Röther J, Papolos A, Kutok J, Hivroz C, Ledeist F, Plogmann K et al.. (2009) ORAI1 deficiency and lack of store-operated Ca2+ entry cause immunodeficiency, myopathy, and ectodermal dysplasia. J Allergy Clin Immunol, 124 (6): 1311-1318.e7. [PMID:20004786]
17. McNally BA, Somasundaram A, Yamashita M, Prakriya M. (2012) Gated regulation of CRAC channel ion selectivity by STIM1. Nature, 482 (7384): 241-5. [PMID:22278058]
18. Muik M, Frischauf I, Derler I, Fahrner M, Bergsmann J, Eder P, Schindl R, Hesch C, Polzinger B, Fritsch R et al.. (2008) Dynamic coupling of the putative coiled-coil domain of ORAI1 with STIM1 mediates ORAI1 channel activation. J Biol Chem, 283 (12): 8014-22. [PMID:18187424]
19. Partiseti M, Le Deist F, Hivroz C, Fischer A, Korn H, Choquet D. (1994) The calcium current activated by T cell receptor and store depletion in human lymphocytes is absent in a primary immunodeficiency. J Biol Chem, 269 (51): 32327-35. [PMID:7798233]
20. Prakriya M, Feske S, Gwack Y, Srikanth S, Rao A, Hogan PG. (2006) Orai1 is an essential pore subunit of the CRAC channel. Nature, 443 (7108): 230-3. [PMID:16921383]
21. Roos J, DiGregorio PJ, Yeromin AV, Ohlsen K, Lioudyno M, Zhang S, Safrina O, Kozak JA, Wagner SL, Cahalan MD et al.. (2005) STIM1, an essential and conserved component of store-operated Ca2+ channel function. J Cell Biol, 169 (3): 435-45. [PMID:15866891]
22. Shaw PJ, Feske S. (2012) Regulation of lymphocyte function by ORAI and STIM proteins in infection and autoimmunity. J Physiol (Lond.), 590 (17): 4157-67. [PMID:22615435]
23. Stauderman KA. (2018) CRAC channels as targets for drug discovery and development. Cell Calcium, 74: 147-159. [PMID:30075400]
24. Thompson JL, Mignen O, Shuttleworth TJ. (2009) The Orai1 severe combined immune deficiency mutation and calcium release-activated Ca2+ channel function in the heterozygous condition. J Biol Chem, 284 (11): 6620-6. [PMID:19075015]
25. Tian C, Du L, Zhou Y, Li M. (2016) Store-operated CRAC channel inhibitors: opportunities and challenges. Future Med Chem, 8 (7): 817-32. [PMID:27149324]
26. Vaeth M, Feske S. (2018) Ion channelopathies of the immune system. Curr Opin Immunol, 52: 39-50. [PMID:29635109]
27. Velicelebi G, Stauderman K, Dunn M, Roos J. (2016) Pancreatitis treatment. Patent number: WO2016138472A1. Assignee: Calcimedica, Inc.. Priority date: 27/02/2015. Publication date: 01/09/2016.
28. Williams RT, Manji SS, Parker NJ, Hancock MS, Van Stekelenburg L, Eid JP, Senior PV, Kazenwadel JS, Shandala T, Saint R et al.. (2001) Identification and characterization of the STIM (stromal interaction molecule) gene family: coding for a novel class of transmembrane proteins. Biochem J, 357 (Pt 3): 673-85. [PMID:11463338]
29. Zhang HZ, Xu XL, Chen HY, Ali S, Wang D, Yu JW, Xu T, Nan FJ. (2015) Discovery and structural optimization of 1-phenyl-3-(1-phenylethyl)urea derivatives as novel inhibitors of CRAC channel. Acta Pharmacol Sin, 36 (9): 1137-44. [PMID:26256403]
30. Zweifach A, Lewis RS. (1993) Mitogen-regulated Ca2+ current of T lymphocytes is activated by depletion of intracellular Ca2+ stores. Proc Natl Acad Sci USA, 90 (13): 6295-9. [PMID:8392195]
Orai channels: Orai1. Last modified on 26/09/2024. Accessed on 14/12/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetoimmunopharmacology.org/GRAC/ObjectDisplayForward?objectId=2964.