Orai1 | Orai channels | IUPHAR Guide to IMMUNOPHARMACOLOGY

Top ▲

Orai1

Target id: 2964

Nomenclature: Orai1

Family: Orai channels

Annotation status:  image of a grey circle Awaiting annotation/under development. Please contact us if you can help with annotation.  » Email us

   GtoImmuPdb view: ON :     Orai1 has curated data in GtoImmuPdb

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
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Gene
OMIM
Orphanet
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia

Download all structure-activity data for this target as a CSV file

Channel Blockers
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Concentration range (M) Voltage-dependent (mV) Reference
CRAC channel inhibitor 1 [PMID: 26256403] Hs - - - - no 26
[26]
Not voltage dependent
CRAC channel inhibitor 5b [PMID: 26256403] Hs - - - - no 26
[26]
Not voltage dependent
Clinically-Relevant Mutations and Pathophysiology
Disease:  Immunodeficiency 9
Description: IMD9 is a severe, autosomal recessive disorder caused by loss-of-function mutations in the ORAI1 gene which result in deficient CRAC channel function, and defective T-cell activation. The disease is characterised by neonatal onset of recurrent infections, congenital myopathy and ectodermal dysplasia.
Synonyms: Immune dysfunction with T-cell inactivation due to calcium entry defect 1
OMIM: 612782
References:  5,11,14,17
Biologically Significant Variants
Type:  Missense mutation
Species:  Human
Description:  A loss-of-function mutation in ORAI1 that ablates CRAC channel-mediated calcium entry and results in defective T cell acttivation. A cause of immunodeficiency 9.
Amino acid change:  R91W
Nucleotide change:  271C-T
SNP accession: 
References:  4-5,16
Type:  Frameshift mutation
Species:  Human
Description:  A frameshift variant that causes premature termination of ORAI1 protein translation. Cuases a a loss-of-function effect on CRAC-channel-mediated calcium influx. A cause of immunodeficiency 9
Amino acid change:  Ala88SerfsTer25
Nucleotide change:  c.258_259insA
SNP accession: 
References:  14,17
Type:  Missense mutation
Species:  Human
Description:  A missense variant of the ORAI1 gene that causes a loss-of function effect on CRAC channel-mediated calcium influx. A cause of immunodeficiency 9
Amino acid change:  A103E
Nucleotide change:  c.308C-A
SNP accession: 
References:  11,14
Type:  Missense mutation
Species:  Human
Description:  A missence variant in the ORAI1 gene, that causes a loss-of function in CRAC channels. A cause of immunodeficiency 9
Amino acid change:  L194P
Nucleotide change:  581T-C
SNP accession: 
References:  14

References

Show »

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. 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.

11. 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]

12. 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]

13. 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]

14. 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]

15. 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]

16. 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]

17. 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]

18. 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]

19. 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]

20. 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]

21. Stauderman KA. (2018) CRAC channels as targets for drug discovery and development. Cell Calcium, 74: 147-159. [PMID:30075400]

22. 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]

23. 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]

24. Vaeth M, Feske S. (2018) Ion channelopathies of the immune system. Curr. Opin. Immunol., 52: 39-50. [PMID:29635109]

25. 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]

26. 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]

27. Zweifach A, Lewis RS. (1993) Mitogen-regulated Ca2+ current of T lymphocytes is activated by depletion of intracellular Ca2+ stores. Proc. Natl. Acad. Sci. U.S.A., 90 (13): 6295-9. [PMID:8392195]

How to cite this page

Orai channels: Orai1. Last modified on 13/09/2018. Accessed on 16/01/2019. IUPHAR/BPS Guide to PHARMACOLOGY, http://guidetoimmunopharmacology.org/GRAC/ObjectDisplayForward?objectId=2964.