Orai1

Immunopharmacology Ligand Target has curated data in GtoImmuPdb

Target id: 2964

Nomenclature: Orai1

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)

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Channel Blockers

Key to terms and symbols

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Ligand		Sp.	Action	Value	Parameter	Concentration range (M)	Voltage-dependent (mV)	Reference
CM4620		Hs	Inhibition	6.9	pIC₅₀	-	no	27
⤷	pIC₅₀ 6.9 (IC₅₀ 1.19x10^-7 M) [27] Not voltage dependent Description: In vitro inhibition of calcium entry mediated by Orai1/STIM1 CRAC channels.
GSK-7975A		Hs	Inhibition	6.4	pIC₅₀	-	no	27
⤷	pIC₅₀ 6.4 (IC₅₀ 3.98x10^-7 M) [27] Not voltage dependent Description: In vitro inhibition of calcium entry mediated by Orai1/STIM1 CRAC channels.
CRAC channel inhibitor 1 [PMID: 26256403]		Hs	-	-	-	-	no	29
⤷	[29] Not voltage dependent
CRAC channel inhibitor 5b [PMID: 26256403]		Hs	-	-	-	-	no	29
⤷	[29] Not voltage dependent
compound 36 [PMID: 34843241]		Hs	Inhibition	-	-	-	no	10
⤷	[10] Not voltage dependent
compound 4k [PMID: 39232360]		Hs	Inhibition	-	-	-	no	14
⤷	[14] Not voltage dependent

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]

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]

Cell Type Associations

Immuno Cell Type:	Natural killer cells
Cell Ontology Term:	natural killer cell (CL:0000623)
Comment:	Orai1 is expressed by NK cells and is involved in degranulation and NK cell-mediated cytotoxicity.
References:	26

Immuno Cell Type:	Mast cells
Cell Ontology Term:	mast cell (CL:0000097)
Comment:	Orai1 on mast cells is involved in their degranulation, histamine release and cytokine production and in the immediate dermal response to an allergen-IgE interaction (a.k.a. passive cutaneous anaphylaxis).
References:	26

Immuno Cell Type:	T cells
Cell Ontology Term:	regulatory T cell (CL:0000815) T-helper 17 cell (CL:0000899) type I NK T cell (CL:0000921)
Comment:	The Orai1 gene is expressed by a variety of T cell subtypes, some of which are specified here.
References:	26

Immuno Process Associations

Immuno Process:

T cell (activation)

Immuno Process:

B cell (activation)

Immuno Disease Associations

Disease Name:	Immunodeficiency 9
Disease Synonyms:	no synonynms
Comment:	Mutations in the human ORAI1 gene cause defective T cell activation and immune dysfunction.
Disease X-refs:	OMIM: 612782
References:	3,19

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:

5,12,16,19

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:	rs118203993
References:	4-5,18

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:	rs786205890
References:	12,16

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:	rs782753385
References:	16

Type:	Frameshift mutation
Species:	Human
Description:	A frameshift variant that causes premature termination of ORAI1 protein translation. Causes 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:	rs878853261
References:	16,19

References

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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]