Affinage

ORAI1

Calcium release-activated calcium channel protein 1 · UniProt Q96D31

Length
301 aa
Mass
32.7 kDa
Annotated
2026-06-10
100 papers in source corpus 44 papers cited in narrative 44 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ORAI1 is the pore-forming subunit of the Ca2+-release-activated Ca2+ (CRAC) channel that mediates store-operated Ca2+ entry (SOCE) across the plasma membrane (PMID:16921383, PMID:16645049). Conserved acidic residues E106 in transmembrane helix 1 and E190 in TM3, together with extracellular D110/D112, line the conduction pathway and set the channel's high Ca2+ selectivity; mutation of E106 abolishes Ca2+ permeation and acts as a dominant-negative (PMID:16921383, PMID:16978865). ORAI1 assembles into multimers that can incorporate the paralogs ORAI2/ORAI3, and gating is driven by the ER Ca2+ sensor STIM1: upon store depletion STIM1 and ORAI1 co-cluster into puncta at ER-PM junctions, where STIM1 bridges the ~12-nm gap and physically couples to ORAI1 to open the channel (PMID:16978865, PMID:17442569, PMID:26351694). Activation proceeds through a defined gating interface in which the STIM1 α3 segment within CAD/SOAR lies adjacent to the cytosolic extension of ORAI1 TM3, and a dimeric SOAR domain cross-links multiple ORAI1 channels to increase clustering and cooperativity (PMID:29581306, PMID:30831274). Recruitment of ORAI1 to STIM1 puncta requires store-depletion-triggered S-acylation at C143 (PMID:34156466), and the channel is negatively regulated by Ca2+-bound calmodulin disrupting the STIM1-ORAI1 complex (PMID:29051492) and by thiol oxidation at C195 locking the channel closed (PMID:27624281). Surface ORAI1 abundance is set by an SGK1/Nedd4-2 ubiquitin axis and NF-κB-driven transcription (PMID:21385992, PMID:22682960). Through this Ca2+-entry activity ORAI1 drives NFAT-dependent transcription and effector functions across immune lineages—mast cell degranulation, T- and B-cell activation and activation-induced cell death, and platelet activation and thrombus formation (PMID:18059270, PMID:18591248, PMID:21873530, PMID:18832659)—and in non-immune contexts controls endothelial proliferation and tube formation, cardiomyocyte hypertrophy, keratinocyte adhesion turnover via a PKCβ-Calpain-FAK pathway, osteoclast fusion, and astrocyte reactivity (PMID:18845811, PMID:20138887, PMID:24277812, PMID:23122304, PMID:37679321). Gain-of-function ORAI1 mutations (P245L, G98S, V107M, T184M) cause tubular aggregate myopathy by either abolishing Ca2+-dependent inactivation or generating constitutively permeable channels (PMID:24591628, PMID:28058752, PMID:30382595).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2006 High

    Established the molecular identity of the long-sought CRAC channel pore, answering whether ORAI1 itself conducts Ca2+ or merely supports the channel.

    Evidence Genome-wide RNAi screen plus mutagenesis of pore-lining acidic residues with patch-clamp electrophysiology

    PMID:16645049 PMID:16921383 PMID:16978865

    Open questions at the time
    • Channel stoichiometry and the atomic architecture of the pore were not resolved
    • Mechanism by which the channel is gated open was unknown
  2. 2006 High

    Showed ORAI1 functions in partnership with STIM1, defining the two-component nature of store-operated Ca2+ entry.

    Evidence Co-overexpression of STIM1 and ORAI1 in HEK293/RBL cells with reconstitution of CRAC current by Ca2+ imaging and electrophysiology

    PMID:16733527 PMID:16766533 PMID:16978865

    Open questions at the time
    • Whether STIM1-ORAI1 coupling was direct or indirect was not yet shown
    • Required stoichiometry between the two proteins was undefined
  3. 2007 High

    Defined paralog relationships, showing ORAI2/ORAI3 can heteromultimerize with ORAI1 and support CRAC current with distinct properties.

    Evidence Dominant-negative E106Q cross-inhibition and pharmacological/electrophysiological comparison in STIM1-expressing HEK293 cells

    PMID:17442569

    Open questions at the time
    • Native heteromer composition in physiological cells not established
    • Functional consequences of paralog mixing in vivo unknown
  4. 2007 High

    Demonstrated the in vivo physiological requirement for ORAI1, beginning with mast cell effector function and allergy.

    Evidence Orai1-knockout mouse with degranulation, cytokine, and in vivo allergy assays

    PMID:18059270

    Open questions at the time
    • Downstream transcriptional program not dissected here
    • Cell-type-specific contributions not separable in global knockout
  5. 2008 High

    Extended ORAI1's essential role to lymphocytes and platelets, linking SOCE to adaptive immunity and hemostasis.

    Evidence Orai1-knockout mice with patch-clamp, Ca2+ imaging, proliferation, and in vivo thrombosis models

    PMID:18591248 PMID:18832659

    Open questions at the time
    • Transcription factors coupling Ca2+ entry to phenotype not yet mapped
    • Tissue-specific versus developmental contributions not separated
  6. 2008 High

    Provided the first dynamic, spatial picture of STIM1-ORAI1 activation, showing conformational rearrangement and co-clustering at immune synapses and ER-PM junctions.

    Evidence Live-cell FRET between tagged STIM1/ORAI1 and confocal imaging at the T cell-dendritic cell synapse with dominant-negative dissection

    PMID:18250319 PMID:18832420 PMID:18987344

    Open questions at the time
    • Molecular basis of the gating conformational change not resolved
    • Recruitment versus gating steps separable functionally but not yet structurally
  7. 2009 High

    Expanded ORAI1 function to proliferative and invasive contexts in non-excitable cells, linking SOCE to endothelial cell cycle and tumor metastasis.

    Evidence RNAi/rescue with cell cycle analysis in endothelial cells and in vivo breast cancer metastasis models with pharmacological SOCE inhibition

    PMID:18845811 PMID:19185847

    Open questions at the time
    • Downstream effectors linking Ca2+ entry to migration not fully defined at this stage
    • Specificity of SOCE pharmacology in vivo limited
  8. 2014 High

    Connected ORAI1 to Mendelian disease, identifying gain-of-function mutations causing tubular aggregate myopathy through altered channel inactivation or constitutive permeability.

    Evidence Heterologous expression of patient mutations (P245L) with patch-clamp measurement of Ca2+-dependent inactivation

    PMID:24591628

    Open questions at the time
    • Tissue-level pathology in muscle not mechanistically connected to channel defect
    • Genotype-phenotype range incomplete
  9. 2018 High

    Resolved how STIM1 amplifies channel activity, showing the dimeric SOAR domain cross-links ORAI1 channels to drive clustering and cooperativity.

    Evidence Concatenated SOAR heterodimers with point mutations, super-resolution microscopy, FRAP, and Ca2+ oscillation measurements

    PMID:29581306

    Open questions at the time
    • Quantitative relationship between cluster size and current not fully defined
    • Physiological tuning of cross-linking in native cells unknown
  10. 2019 Medium

    Defined the STIM1-ORAI1 gating interface, distinguishing binding from the coupling step that opens the channel.

    Evidence Cysteine crosslinking and patch-clamp with STIM1 α3 mutants mapping proximity to ORAI1 TM3

    PMID:30831274

    Open questions at the time
    • Crosslinking and electrophysiology from a single lab without structural confirmation
    • Allosteric pathway from interface to pore not resolved
  11. 2017 Medium

    Resolved that channel-regulatory inputs include calmodulin-mediated inactivation and redox locking, defining negative-feedback control of ORAI1.

    Evidence Biochemical CaM-STIM1 binding mapping and oxidomimetic C195D mutagenesis with single-particle tracking and functional assays

    PMID:27624281 PMID:29051492

    Open questions at the time
    • Redox findings rest on a single lab with oxidomimetic surrogates
    • Integration of multiple negative regulators in vivo not established
  12. 2021 High

    Identified a post-translational switch required for channel recruitment, showing store-depletion-triggered S-acylation at C143 enables ORAI1 trafficking into STIM1 puncta.

    Evidence Acyl-RAC biochemistry, C143 mutagenesis, Ca2+ imaging, and STIM1 puncta colocalization

    PMID:34156466

    Open questions at the time
    • Enzyme(s) catalyzing the S-acylation not identified
    • Kinetic relationship to STIM1 oligomerization not resolved
  13. 2023 High

    Broadened the physiological reach of ORAI1 to glia and CNS function, linking astrocyte SOCE to inflammatory gene expression and behavior.

    Evidence Astrocyte-specific Orai1 knockout mice with transcriptomics, metabolomics, electrophysiology, and behavioral testing

    PMID:37679321

    Open questions at the time
    • Direct Ca2+-to-transcription effectors in astrocytes not fully mapped
    • Neuronal versus glial circuit contributions not separated

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the many regulatory layers (S-acylation, calmodulin, redox, glycosylation, PKC phosphorylation, SGK1/Nedd4-2, NF-κB) are integrated to set context-specific ORAI1 activity, and the atomic structure of the gated STIM1-ORAI1 complex, remain unresolved.
  • No unified quantitative model of competing regulators
  • No high-resolution structure of the activated STIM1-ORAI1 gating complex in the timeline

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 3 GO:0060089 molecular transducer activity 2
Localization
GO:0005886 plasma membrane 3
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3 R-HSA-168256 Immune System 3 R-HSA-109582 Hemostasis 1
Partners
CALM1ORAI2ORAI3PTGER4RYR1STIM1STIM2TRPC1
Complex memberships
CRAC channel

Evidence

Reading pass · 44 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 Orai1 is a pore subunit of the CRAC channel: E106D and E190Q substitutions in transmembrane helices 1 and 3 diminish Ca2+ influx, increase current carried by monovalent cations, and render the channel permeable to Cs+, demonstrating that Orai1 lines the ion-conducting pore. Site-directed mutagenesis of conserved acidic residues in transmembrane segments combined with patch-clamp electrophysiology Nature High 16921383
2006 CRACM1 (Orai1) is a plasma membrane-resident protein essential for store-operated Ca2+ entry; RNAi-mediated knockdown of CRACM1 disrupts CRAC current activation in human cells. Genome-wide RNAi screen in Drosophila cells followed by secondary patch-clamp screen; RNAi knockdown in human cells Science High 16645049
2006 Co-overexpression of STIM1 and CRACM1/Orai1 reconstitutes and massively potentiates CRAC current (I_CRAC), demonstrating a functional interaction between the two proteins and that each limits store-operated currents. Overexpression of STIM1 and CRACM1 in HEK293 cells combined with patch-clamp electrophysiology Nature Cell Biology High 16733527 16766533
2006 CRACM1 forms multimeric assemblies (homomultimers) that bind STIM1; acidic residues E106 (TM1), E190 (TM3), and D110/D112 in the extracellular loop contribute to ionic selectivity of the CRAC channel pore. E106Q acts as a dominant-negative mutant. Co-immunoprecipitation of CRACM1 multimers; site-directed mutagenesis combined with patch-clamp electrophysiology Current Biology High 16978865
2006 Orai1 expressed alone strongly reduces store-operated Ca2+ entry in HEK293 cells, but co-expression with STIM1 causes up to 103-fold increase in Ca2+ entry, all of which is store-dependent, indicating Orai1 is the plasma membrane channel component and that a specific stoichiometry with STIM1 is required. Ca2+ imaging and patch-clamp electrophysiology in HEK293 and RBL cells with individual and combined overexpression Journal of Biological Chemistry High 16766533
2007 CRACM2 and CRACM3 (Orai2 and Orai3) can potentiate I_CRAC when co-expressed with STIM1 and can form heteromultimeric complexes with CRACM1 (Orai1), as shown by the dominant-negative E106Q mutation of CRACM1 suppressing all three homologs. Each paralog exhibits distinct ion selectivity, 2-APB pharmacology, and Ca2+-dependent feedback regulation. Patch-clamp electrophysiology; dominant-negative mutant cross-inhibition; pharmacological analysis in HEK293 cells stably expressing STIM1 Current Biology High 17442569
2007 CRACM1-deficient (Orai1-knockout) mice show grossly defective mast cell degranulation and cytokine secretion, and impaired allergic reactions in vivo, establishing Orai1 as the pore subunit essential for mast cell Ca2+ entry and effector function. Gene-targeted Orai1-knockout mouse; mast cell degranulation assays; cytokine secretion; in vivo allergy models Nature Immunology High 18059270
2008 STIM1 and Orai1 undergo a STIM1-dependent conformational change upon store depletion; FRET shows increased STIM1-Orai1 interaction and a decline in Orai1-Orai1 FRET, indicating molecular rearrangements within Orai1 multimers during channel activation that are absent without STIM1 co-expression and abolished in Orai1 mutants with impaired STIM1 interaction. Live-cell FRET microscopy between fluorescently tagged STIM1 and Orai1 or Orai1-Orai1 pairs; Orai1 mutant analysis Journal of Physiology High 18832420
2008 STIM1 and Orai1 co-cluster at the immunological synapse between primary human T cells and dendritic cells, where Ca2+ influx is localized; expression of dominant-negative Orai1 blocks T cell Ca2+ signaling but does not prevent initial accumulation of STIM1, Orai1, or CD3 at the contact zone. Confocal imaging; Ca2+ imaging with EGTA; dominant-negative Orai1 expression; co-localization with TCR and costimulatory molecules PNAS High 18250319
2008 Orai1 is the platelet store-operated Ca2+ (SOC) channel; Orai1-deficient mice display severely defective SOCE, agonist-induced Ca2+ responses, impaired platelet activation and thrombus formation, and resistance to thromboembolism and arterial thrombosis, with only mild bleeding prolongation. Orai1-knockout mouse; Ca2+ imaging in platelets; flow chamber thrombus assays; pulmonary thromboembolism, arterial thrombosis, and stroke models in vivo Blood High 18832659
2008 STIM1-Orai1 nanoscale interaction detected by FRET depends quantitatively on the extent of store depletion and on electrostatic interactions via acidic residues in the cytoplasmic segment of Orai1; sphingosine derivatives inhibit Orai1-STIM1 association and Ca2+ influx in parallel. FRET between STIM1-mRFP and AcGFP-Orai1; mutagenesis of cytoplasmic acidic residues; pharmacological inhibition with sphingosine derivatives; confocal microscopy Molecular Biology of the Cell Medium 18987344
2008 Orai1-null mice show reduction in store-operated Ca2+ entry and CRAC currents in T cells and reduced Ca2+ influx and proliferation in B cells, establishing Orai1 as a pore subunit required for lymphocyte Ca2+ entry and function. Orai1 gene-targeted knockout mice; patch-clamp; Ca2+ imaging in T and B cells; proliferation assays Molecular and Cellular Biology High 18591248
2009 Orai1 and STIM1 mediate CRAC current and store-operated Ca2+ entry in endothelial cells; RNA silencing of either Stim1 or Orai1 abolishes SOCE and I_CRAC, and inhibits endothelial cell proliferation causing cell cycle arrest at S and G2/M phases. RNA silencing; Ca2+ imaging; patch-clamp electrophysiology; rescue by ectopic expression; cell cycle analysis by flow cytometry Circulation Research High 18845811
2009 Orai1 and STIM1 are essential for breast tumor cell migration in vitro and metastasis in vivo; RNAi reduction of Orai1 or STIM1 in highly metastatic breast cancer cells or pharmacological inhibition of store-operated Ca2+ channels decreases tumor metastasis in mice. RNAi knockdown; in vitro migration assays; in vivo tumor metastasis mouse models; pharmacological SOCE inhibition Cancer Cell High 19185847
2010 Orai1 knockdown in neonatal cardiomyocytes significantly diminishes basal cell size, ANP/BNP mRNA levels, and calcineurin (CnA) signaling activity, and completely abrogates phenylephrine-mediated hypertrophic growth and CamKII/ERK1/2 activation, establishing Orai1 as a regulator of cardiomyocyte hypertrophic signaling. siRNA knockdown of Orai1 in neonatal rat ventricular cardiomyocytes; Ca2+ imaging; phosphoprotein analysis; mRNA expression Journal of Molecular and Cellular Cardiology Medium 20138887
2011 SGK1 upregulates membrane Orai1 protein abundance, I_CRAC, and SOCE; constitutively active SGK1 (S422D) increases Orai1 surface expression and SOCE, whereas ubiquitin ligase Nedd4-2 (an SGK1-inhibited target) downregulates SOCE; SGK1 prevents Nedd4-2 interaction with Orai1, thereby protecting Orai1 from degradation. Heterologous expression of constitutively active/inactive SGK1 mutants; siRNA; SOCE measurement by Fura-2; patch-clamp; SGK1-knockout mast cells FASEB Journal High 21385992
2011 ORAI1-mediated Ca2+ entry activates the NFAT pathway to drive activation-induced T cell death; ORAI1-deficient CD4+ T cells show reduced mitochondrial Ca2+ uptake, altered pro-/anti-apoptotic gene expression (Fas ligand, Noxa, Mcl-1), and resistance to stimulation-induced death; constitutively active NFAT rescues cell death in ORAI1-deficient T cells. Orai1-knockout mice; adoptive transfer; anti-CD3 injection; NFAT nuclear localization; ORAI1 mutant expression to titrate Ca2+ levels; flow cytometry Journal of Immunology High 21873530
2011 Orai1 disruption by siRNA or dominant-negative Orai1 inhibits store-operated Ca2+ entry, VEGF-evoked Ca2+ entry, cell migration, and in vitro tube formation in human umbilical vein endothelial cells; exogenous wild-type Orai1 rescues tube formation. siRNA; dominant-negative Orai1; Ca2+ imaging; migration assay; tube formation assay; rescue by wild-type Orai1 Circulation Research Medium 21441136
2013 Orai1 controls keratinocyte proliferation and polarized motility in the basal epidermis; Orai1-mediated Ca2+ entry enhances focal adhesion turnover via a PKCβ-Calpain-focal adhesion kinase (FAK) pathway; Orai1 loss alters keratinocyte differentiation in vitro and in vivo. Orai1-knockout mice; primary keratinocytes; Ca2+ imaging; focal adhesion assays; pharmacological and genetic manipulation of PKCβ/Calpain/FAK PNAS High 24277812
2014 STIM1- and Orai1-mediated Ca2+ oscillations promote melanoma invasion by orchestrating invadopodium assembly via Src activation and by regulating MT1-MMP recycling to the plasma membrane; Orai1 blockade entraps MT1-MMP in endocytic compartments and inhibits ECM degradation. STIM1 knockdown; Orai1 pharmacological blockade; live-cell imaging; invadopodium assays; MT1-MMP localization; Src activity assay; xenograft metastasis model Journal of Cell Biology High 25404747
2014 Gain-of-function mutation ORAI1 P245L causes tubular aggregate myopathy-like syndrome by suppressing slow Ca2+-dependent inactivation of the CRAC channel (rather than making it constitutively active), while STIM1 R304W causes constitutive CRAC channel activation. Heterologous expression of patient mutations; patch-clamp electrophysiology measuring Ca2+-dependent inactivation; zebrafish model for STIM1 R304W PNAS High 24591628
2015 Calsequestrin 1 (CSQ1) interacts physically with STIM1; monomeric CSQ1 induced by store depletion or trifluoperazine enhances the CSQ1-STIM1 interaction, which inhibits STIM1 oligomerization and suppresses the STIM1-Orai1 interaction and SOCE, providing a retrograde brake on Ca2+ entry. Co-immunoprecipitation; overexpression of CSQ1 deletion mutants; Ca2+ imaging; SOCE measurement in HEK293 cells Scientific Reports Medium 26087026
2015 STIM1 and Orai1 cluster into puncta at ER-PM junctions upon store depletion; electron microscopy reveals STIM1 bridges the 12-nm ER-PM gap and Orai1 particles aggregate into sharply delimited puncta on membrane subdomains; stoichiometry of Orai1 channels is unchanged by store depletion, STIM1 co-expression, or the L273D mutation. Transmission and freeze-fracture electron microscopy of STIM1- and Orai1-transfected HEK293 cells with and without thapsigargin treatment PNAS High 26351694
2015 Orai1 is deleted in mice with Orai1 deficiency and osteoclasts show abolished SOCE, impaired cell fusion during osteoclastogenesis, and reduced resorption pit size; Orai1-deficient mice develop osteopenia with decreased bone mineral density; osteoblasts lacking Orai1-mediated SOCE show impaired mineral deposition but normal differentiation. Orai1-knockout mice; in vitro osteoclast and osteoblast differentiation; Ca2+ imaging; resorption pit assay; bone densitometry Cell Calcium High 23122304
2016 N-glycosylation of Orai1 at N223 is cell type-specific and modulates SOCE; mutation of the glycosylation site (Orai1-N223A) enhances SOCE in Jurkat T cells; knockdown of sialyltransferase ST6GAL1, which adds α-2,6-linked sialic acids to Orai1 glycans, increases Ca2+ entry, suggesting that Siglec lectins binding sialylated Orai1 attenuate SOCE. Western blot; lectin-binding assays; Ca2+ imaging; patch-clamp; site-directed mutagenesis of N223; siRNA knockdown of ST6GAL1 Science Signaling Medium 26956484
2016 Protein kinase C (PKC), a downstream target of Wnt5A, phosphorylates Orai1 and suppresses SOCE in invasive melanoma; co-expression of STIM1 with a PKC-insensitive Orai1 mutant fully restores SOCE in invasive melanoma cells, while wild-type Orai1+STIM1 fails to restore SOCE. Ca2+ imaging; patch-clamp; PKC inhibition; expression of PKC-insensitive Orai1 mutant; fluorescence microscopy in patient-derived melanoma cells Molecular and Cellular Biology Medium 26055321
2016 Orai1-dependent Ca2+ entry in macrophages promotes foam cell formation via calcineurin activation and apoptosis signal-regulating kinase 1 (ASK1)/JNK/p38 signaling leading to scavenger receptor A upregulation; Orai1 knockdown in ApoE-/- mice inhibits atherosclerotic plaque development. siRNA knockdown; Ca2+ imaging; pharmacological inhibitors; adenoviral Orai1 siRNA in ApoE-/- mice; immunostaining Arteriosclerosis Thrombosis and Vascular Biology Medium 26916730
2017 Gain-of-function ORAI1 mutations G98S and V107M generate constitutively permeable channels independent of STIM1, whereas T184M alters channel permeability only in the presence of STIM1, demonstrating a mutation-dependent pathomechanism for tubular aggregate myopathy. Patch-clamp electrophysiology and Ca2+ imaging of mutant ORAI1 channels expressed in HEK cells; functional characterization with/without STIM1 Human Mutation High 28058752
2017 Ca2+-bound calmodulin (Ca2+-CaM) binds to the core region of activated STIM1 adjacent to the STIM1-Orai1 coupling region; this interaction disrupts the STIM1-Orai1 complex and disassembles STIM1 oligomers, facilitating slow Ca2+-dependent inactivation of Orai1 channels. Biochemical binding assays; CaM-binding site mapping in STIM1; functional Ca2+ imaging and patch-clamp with wild-type and constitutively active STIM1 mutants Nature Communications High 29051492
2018 STIM1 cross-links Orai1 channels via its dimeric SOAR domain: each SOAR monomer independently interacts with single Orai1 subunits, causing Orai1 channel clustering (shown by super-resolution imaging and FRAP), and increasing cooperativity and efficacy of Orai1 channel function; STIM2.1, a naturally occurring STIM2 splice variant with an 8-aa insert in SOAR, activates but cannot cross-link Orai1, thereby suppressing sustained Ca2+ oscillations and protecting against Ca2+ overload. Concatenated SOAR heterodimers with point mutations; super-resolution microscopy; FRAP; Ca2+ oscillation measurements; co-expression experiments PNAS High 29581306
2018 ORAI1, STIM1, STIM2, and RYR1 cooperate to generate subsecond Ca2+ microdomains in T cells; super-resolution microscopy identified preformed ~300-nm subplasmalemmal clusters of colocalized ORAI1, RYR1, and STIM1 in resting T cells; upon TCR stimulation, NAADP-evoked Ca2+ release through RYR1 coordinates with ORAI1 to rapidly amplify Ca2+ microdomain number. Super-resolution microscopy; co-immunoprecipitation; FRET; NAADP signaling; knockout cell analysis; Ca2+ imaging Science Signaling High 30563862
2018 TAM-associated ORAI1 mutation V107M (TM1) constitutively activates the channel, decreases Ca2+ selectivity, and confers resistance to acidic pH inhibition; T184M (TM3) constitutively activates the channel but requires STIM1 for gain-of-function and retains sensitivity to reactive oxygen species; both mutants are blocked by low concentrations of GSK-7975A except G98S. Patch-clamp electrophysiology; Ca2+ imaging; molecular dynamics simulations; expression in Stim1-/-/Stim2-/- MEFs; primary human myoblasts Journal of Physiology High 30382595
2019 A novel STIM1 α3 helical segment (aa 400-403) within CAD/SOAR is not required for STIM1-Orai1 binding but is essential for coupling STIM1 interaction into Orai1 channel gating; cysteine crosslinking revealed close proximity of STIM1 α3 to the cytosolic extension of Orai1 TM3, defining a STIM1-Orai1 gating interface (SOGI). Cysteine crosslinking; functional patch-clamp and Ca2+ imaging with STIM1 α3 mutants; proximity assay Cell Calcium Medium 30831274
2019 Septin 4 facilitates STIM1-ORAI1 Ca2+ signaling by regulating the number of ER-PM junctions rather than by directly co-localizing with ORAI1 or specifying ORAI1 distribution; ORAI1 is recruited to junctions solely through its interaction with STIM proteins, while septins increase junction number and enhance STIM1-ORAI1 interactions within junctions. Super-resolution live-cell imaging of ORAI1, STIM1, and septin 4; co-localization analysis; STIM/septin perturbation Scientific Reports Medium 31346209
2019 Prostaglandin E2 receptor EP4 forms complexes with Orai1 and TRPC1 (but not STIM1) and activates store-independent Ca2+ influx through Orai1 via PI3K; EP4 agonist-induced ERK phosphorylation requires Orai1; Orai1 knockdown abrogates EP4-mediated cell migration in oral cancer cells. Co-immunoprecipitation; siRNA knockdown; Ca2+ imaging; ERK phosphorylation assay; cell migration assay; in vivo lung metastasis model Cancer Science Medium 31755615
2021 Orai1 undergoes rapid and transient S-acylation at cysteine C143 upon ER Ca2+ store depletion; this modification is required for Orai1-mediated Ca2+ entry and for recruitment of Orai1 to STIM1 puncta at ER-PM junctions. Biochemical S-acylation detection (acyl-RAC); site-directed mutagenesis of C143; Ca2+ imaging; STIM1 puncta co-localization assay Journal of Cell Science High 34156466
2016 Thiol oxidation of Orai1 at C195 (the primary redox sensor) leads to intramolecular interaction between oxidized/oxidomimetic C195D and S239 of TM4, locking the channel in a closed conformation; oxidation of C195 also reduces subunit interaction and slows Orai1 diffusion. Oxidomimetic mutagenesis (C195D); SOCE measurement; single-particle tracking; molecular dynamics; experimental validation of intramolecular interaction Scientific Reports Medium 27624281
2023 In astrocytes, Orai1 is required for Ca2+ signaling, hippocampal inflammatory gene expression, and inhibitory neurotransmission; astrocyte-specific Orai1 knockout reduces ATP production, downregulates inflammation/immunity genes, blunts LPS-induced astrocyte Ca2+ signaling and inhibitory neurotransmission in hippocampus, and ameliorates LPS-evoked depression-like behaviors. Astrocyte-specific Orai1 knockout mice; transcriptomics; metabolomics; Ca2+ imaging; electrophysiology; behavioral tests Nature Communications High 37679321
2013 Native STIM2 and ORAI1 form endogenous complexes in cortical neurons that are sensitive to low Ca2+ but not to thapsigargin-induced store depletion; complex number increases when intracellular Ca2+ is lowered by BAPTA-AM or low-Ca2+ medium, but not by thapsigargin, indicating a thapsigargin-insensitive STIM2-ORAI1 interaction mode in neurons. Co-immunoprecipitation of endogenous proteins; proximity ligation assay (PLA); Fura-2 Ca2+ imaging in cortical neurons Journal of Neurochemistry Medium 23711249
2015 ORAI1 expression is regulated by NF-κB; SGK1 upregulates NF-κB activity to increase Orai1 (and STIM1) transcription, while AMPK activates Nedd4-2 ubiquitin ligase to promote Orai1 degradation; these opposing kinases regulate plasma membrane Orai1 levels and SOCE. Transcription factor binding assay (NF-κB promoter); SGK1 and AMPK gain/loss of function; Western blot; SOCE measurement Cell Calcium Medium 22682960
2021 ORAI1-mediated homeostatic Ca2+ signaling maintains tonic type I IFN levels through Ca2+-dependent transcription factors AP-1 and MEF2C; ORAI1 knockout cells show reduced basal cytoplasmic Ca2+, impaired tonic IFN-β expression, and increased susceptibility to SARS-CoV-2 infection, while STIM1 knockout cells show enhanced IFN-I response and resistance. ORAI1 and STIM1 CRISPR knockout in HEK293-ACE2 cells; transcriptome analysis; SARS-CoV-2 infection; ORAI1 blocker/agonist modulation; IFN-β expression assay Journal of Immunology Medium 34819389
2022 Orai1 channels are localized predominantly in the apical plasma membrane of pancreatic ductal cells; selective Orai1 inhibition impairs STIM1-dependent Ca2+ influx evoked by bile acids or ethanol metabolites, protects ductal secretory function, and maintains exocrine pancreatic secretion in in vivo acute pancreatitis models. Immunofluorescence localization; selective Orai1 inhibitor CM5480; Ca2+ imaging; in vitro secretion assays; in vivo acute pancreatitis models Journal of Physiology Medium 35081662
2023 In entotic cancer cells, SEPTIN filaments control polarized distribution of Orai1 at the plasma membrane; local MLCK activation by Orai1-mediated Ca2+/CaM at this site drives MLC phosphorylation and actomyosin contraction required for cell internalization (entosis); inhibition of SEPTIN, Orai1, or MLCK suppresses entosis. Ca2+ imaging with spatiotemporal analysis; SEPTIN/Orai1/MLCK inhibitors and knockdown; MLC phosphorylation assay; immunostaining Advanced Science Medium 36960682
2015 SPLUNC1 (short palate lung and nasal epithelial clone 1) protein inhibits Orai1 and SOCE via its C-terminal α6 region; FRET shows direct interaction between α6 and Orai1; inhaled α6 peptidomimetics reduce Orai1 levels and eosinophilia/neutrophilia in HDM-exposed mice. FRET; Ca2+ imaging; FRAP; TIRF microscopy; Western blot; in vivo inhalation model in wild-type and SPLUNC1-/- mice American Journal of Respiratory Cell and Molecular Biology Medium 34807800

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Orai1 is an essential pore subunit of the CRAC channel. Nature 1141 16921383
2006 CRACM1 is a plasma membrane protein essential for store-operated Ca2+ entry. Science (New York, N.Y.) 1138 16645049
2009 Orai1 and STIM1 are critical for breast tumor cell migration and metastasis. Cancer cell 574 19185847
2006 Amplification of CRAC current by STIM1 and CRACM1 (Orai1). Nature cell biology 484 16733527
2006 CRACM1 multimers form the ion-selective pore of the CRAC channel. Current biology : CB 481 16978865
2006 Orai1 and STIM reconstitute store-operated calcium channel function. The Journal of biological chemistry 464 16766533
2015 Diseases caused by mutations in ORAI1 and STIM1. Annals of the New York Academy of Sciences 374 26469693
2007 Defective mast cell effector functions in mice lacking the CRACM1 pore subunit of store-operated calcium release-activated calcium channels. Nature immunology 342 18059270
2008 Stim1 and Orai1 mediate CRAC currents and store-operated calcium entry important for endothelial cell proliferation. Circulation research 326 18845811
2007 CRACM1, CRACM2, and CRACM3 are store-operated Ca2+ channels with distinct functional properties. Current biology : CB 315 17442569
2009 ORAI1 deficiency and lack of store-operated Ca2+ entry cause immunodeficiency, myopathy, and ectodermal dysplasia. The Journal of allergy and clinical immunology 274 20004786
2008 Hair loss and defective T- and B-cell function in mice lacking ORAI1. Molecular and cellular biology 254 18591248
2008 Orai1 (CRACM1) is the platelet SOC channel and essential for pathological thrombus formation. Blood 232 18832659
2008 Orai1 and STIM1 move to the immunological synapse and are up-regulated during T cell activation. Proceedings of the National Academy of Sciences of the United States of America 223 18250319
2014 Activating mutations in STIM1 and ORAI1 cause overlapping syndromes of tubular myopathy and congenital miosis. Proceedings of the National Academy of Sciences of the United States of America 210 24591628
2016 TRPC1, Orai1, and STIM1 in SOCE: Friends in tight spaces. Cell calcium 187 28089266
2008 STIM1-Orai1 interactions and Orai1 conformational changes revealed by live-cell FRET microscopy. The Journal of physiology 184 18832420
2011 Orai1 and CRAC channel dependence of VEGF-activated Ca2+ entry and endothelial tube formation. Circulation research 172 21441136
2013 STIM1 and Orai1 mediate CRAC channel activity and are essential for human glioblastoma invasion. Pflugers Archiv : European journal of physiology 164 23515871
2010 Immunodeficiency due to mutations in ORAI1 and STIM1. Clinical immunology (Orlando, Fla.) 146 20189884
2014 STIM1- and Orai1-mediated Ca(2+) oscillation orchestrates invadopodium formation and melanoma invasion. The Journal of cell biology 139 25404747
2010 Orai1 and Stim1 regulate normal and hypertrophic growth in cardiomyocytes. Journal of molecular and cellular cardiology 130 20138887
2014 Elevated Orai1 expression mediates tumor-promoting intracellular Ca2+ oscillations in human esophageal squamous cell carcinoma. Oncotarget 129 24797725
2008 Molecular clustering of STIM1 with Orai1/CRACM1 at the plasma membrane depends dynamically on depletion of Ca2+ stores and on electrostatic interactions. Molecular biology of the cell 122 18987344
2009 An endoplasmic reticulum/plasma membrane junction: STIM1/Orai1/TRPCs. FEBS letters 112 19944100
2013 STIM1/Orai1-mediated SOCE: current perspectives and potential roles in cardiac function and pathology. American journal of physiology. Heart and circulatory physiology 111 23792674
2023 Astrocyte reactivity and inflammation-induced depression-like behaviors are regulated by Orai1 calcium channels. Nature communications 107 37679321
2014 Orai1 and STIM1 mediate SOCE and contribute to apoptotic resistance of pancreatic adenocarcinoma. Biochimica et biophysica acta 103 24583265
2011 Calcium entry via ORAI1 regulates glioblastoma cell proliferation and apoptosis. Experimental and molecular pathology 94 21945734
2017 ORAI1 Mutations with Distinct Channel Gating Defects in Tubular Aggregate Myopathy. Human mutation 91 28058752
2018 STIM1 activation of Orai1. Cell calcium 87 30530091
2015 The STIM1-ORAI1 microdomain. Cell calcium 86 26215475
2011 Stimulation of Ca2+-channel Orai1/STIM1 by serum- and glucocorticoid-inducible kinase 1 (SGK1). FASEB journal : official publication of the Federation of American Societies for Experimental Biology 83 21385992
2013 Orai1-NFAT signalling pathway triggered by T cell receptor stimulation. Molecules and cells 82 23483280
2016 Inhibition of Orai1 Store-Operated Calcium Channel Prevents Foam Cell Formation and Atherosclerosis. Arteriosclerosis, thrombosis, and vascular biology 76 26916730
2014 STIM1, STIM2, and Orai1 regulate store-operated calcium entry and purinergic activation of microglia. Glia 76 25471906
2011 Contribution of TRPC1 and Orai1 to Ca(2+) entry activated by store depletion. Advances in experimental medicine and biology 75 21290310
2011 ORAI1 deficiency impairs activated T cell death and enhances T cell survival. Journal of immunology (Baltimore, Md. : 1950) 70 21873530
2022 Orai1 Inhibitors as Potential Treatments for Pulmonary Arterial Hypertension. Circulation research 67 36164973
2018 ORAI1, STIM1/2, and RYR1 shape subsecond Ca2+ microdomains upon T cell activation. Science signaling 66 30563862
2018 Ca2+ handling remodeling and STIM1L/Orai1/TRPC1/TRPC4 upregulation in monocrotaline-induced right ventricular hypertrophy. Journal of molecular and cellular cardiology 65 29634917
2017 The STIM-Orai coupling interface and gating of the Orai1 channel. Cell calcium 63 28087079
2013 ORAI1 calcium channel orchestrates skin homeostasis. Proceedings of the National Academy of Sciences of the United States of America 63 24277812
2012 Regulation of Orai1/STIM1 by the kinases SGK1 and AMPK. Cell calcium 60 22682960
2011 Orai1/CRACM1 overexpression suppresses cell proliferation via attenuation of the store-operated calcium influx-mediated signalling pathway in A549 lung cancer cells. Biochimica et biophysica acta 58 21782006
2020 Orai1 Channel Inhibition Preserves Left Ventricular Systolic Function and Normal Ca2+ Handling After Pressure Overload. Circulation 57 31906693
2018 Cross-linking of Orai1 channels by STIM proteins. Proceedings of the National Academy of Sciences of the United States of America 56 29581306
2019 Molecular basis of allosteric Orai1 channel activation by STIM1. The Journal of physiology 55 30950063
2013 Regulation of STIM1/Orai1-dependent Ca2+ signalling in platelets. Thrombosis and haemostasis 54 23846758
2013 Native STIM2 and ORAI1 proteins form a calcium-sensitive and thapsigargin-insensitive complex in cortical neurons. Journal of neurochemistry 53 23711249
2012 Orai1 calcium channels in the vasculature. Pflugers Archiv : European journal of physiology 53 22402985
2019 Calcium channel Orai1 promotes lymphocyte IL-17 expression and progressive kidney injury. The Journal of clinical investigation 51 31415242
2015 Nanoscale patterning of STIM1 and Orai1 during store-operated Ca2+ entry. Proceedings of the National Academy of Sciences of the United States of America 51 26351694
2015 NFκB-sensitive Orai1 expression in the regulation of FGF23 release. Journal of molecular medicine (Berlin, Germany) 48 26631141
2016 STIMs and Orai1 regulate cytokine production in spinal astrocytes. Journal of neuroinflammation 47 27245842
2016 Orai1 and Orai2 mediate store-operated calcium entry that regulates HL60 cell migration and FAK phosphorylation. Biochimica et biophysica acta. Molecular cell research 47 27865925
2015 Retrograde regulation of STIM1-Orai1 interaction and store-operated Ca2+ entry by calsequestrin. Scientific reports 47 26087026
2017 Calmodulin dissociates the STIM1-Orai1 complex and STIM1 oligomers. Nature communications 46 29051492
2015 STIM1/ORAI1-mediated Ca2+ Influx Regulates Enolase-1 Exteriorization. The Journal of biological chemistry 46 25805497
2015 The ER/PM microdomain, PI(4,5)P₂ and the regulation of STIM1-Orai1 channel function. Cell calcium 46 25843208
2019 A novel STIM1-Orai1 gating interface essential for CRAC channel activation. Cell calcium 45 30831274
2016 Variations in ORAI1 Gene Associated with Kawasaki Disease. PloS one 45 26789410
2015 Novel Protein Kinase C-Mediated Control of Orai1 Function in Invasive Melanoma. Molecular and cellular biology 44 26055321
2016 STIM and Orai1 Variants in Store-Operated Calcium Entry. Frontiers in pharmacology 42 26793113
2012 Deletion of Orai1 alters expression of multiple genes during osteoclast and osteoblast maturation. Cell calcium 42 23122304
2020 ORAI1 and ORAI2 modulate murine neutrophil calcium signaling, cellular activation, and host defense. Proceedings of the National Academy of Sciences of the United States of America 41 32929002
2018 ORAI1 channel gating and selectivity is differentially altered by natural mutations in the first or third transmembrane domain. The Journal of physiology 37 30382595
2016 Cell type-specific glycosylation of Orai1 modulates store-operated Ca2+ entry. Science signaling 37 26956484
2015 Orai1 controls C5a-induced neutrophil recruitment in inflammation. European journal of immunology 36 25912155
2019 TRPC1 and ORAI1 channels in colon cancer. Cell calcium 34 31203007
2016 Thiol dependent intramolecular locking of Orai1 channels. Scientific reports 33 27624281
2018 Hypoxia-induced upregulation of Orai1 drives colon cancer invasiveness and angiogenesis. European journal of pharmacology 32 29753044
2019 Septins organize endoplasmic reticulum-plasma membrane junctions for STIM1-ORAI1 calcium signalling. Scientific reports 31 31346209
2013 Alternative forms of the store-operated calcium entry mediators, STIM1 and Orai1. Current topics in membranes 30 23890113
2019 Store-independent Orai1-mediated Ca2+ entry and cancer. Cell calcium 29 30921687
2010 Expression and association of TRPC subtypes with Orai1 and STIM1 in human parathyroid. Journal of molecular endocrinology 29 20194530
2007 Store-operated Orai1 and IP3 receptor-operated TRPC1 channel. Channels (Austin, Tex.) 29 18711860
2017 Lithium Sensitive ORAI1 Expression, Store Operated Ca2+ Entry and Suicidal Death of Neurons in Chorea-Acanthocytosis. Scientific reports 28 28743945
2022 Bile acid- and ethanol-mediated activation of Orai1 damages pancreatic ductal secretion in acute pancreatitis. The Journal of physiology 27 35081662
2017 Intra-articular lentivirus-mediated gene therapy targeting CRACM1 for the treatment of collagen-induced arthritis. Journal of pharmacological sciences 27 28258822
2013 Are Orai1 and Orai3 channels more important than calcium influx for cell proliferation? Biochimica et biophysica acta 27 24321771
2019 Prostaglandin E2 receptor EP4 regulates cell migration through Orai1. Cancer science 26 31755615
2015 Orai/CRACM1 and KCa3.1 ion channels interact in the human lung mast cell plasma membrane. Cell communication and signaling : CCS 26 26177720
2021 SARAF and Orai1 Contribute to Endothelial Cell Activation and Angiogenesis. Frontiers in cell and developmental biology 25 33748129
2023 Orai1 calcium channel inhibition prevents progression of chronic pancreatitis. JCI insight 24 37227782
2022 A SPLUNC1 Peptidomimetic Inhibits Orai1 and Reduces Inflammation in a Murine Allergic Asthma Model. American journal of respiratory cell and molecular biology 23 34807800
2013 Involvement of STIM1 and Orai1 in EGF-mediated cell growth in retinal pigment epithelial cells. Journal of biomedical science 23 23800047
2013 TGFβ1 and SGK1-sensitive store-operated Ca2+ entry and Orai1 expression in endometrial Ishikawa cells. Molecular human reproduction 23 24043696
2019 Functional consequences of enhanced expression of STIM1 and Orai1 in Huh-7 hepatocellular carcinoma tumor-initiating cells. BMC cancer 22 31366337
2011 STIM1 and Orai1: novel targets for vascular diseases? Science China. Life sciences 22 21786201
2018 STIM1 and Orai1 regulate Ca2+ microdomains for activation of transcription. Biochimica et biophysica acta. Molecular cell research 21 30408546
2017 NFAT5-sensitive Orai1 expression and store-operated Ca2+ entry in megakaryocytes. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 21 28446591
2016 Chorein Sensitive Orai1 Expression and Store Operated Ca2+ Entry in Rhabdomyosarcoma Cells. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 21 27960157
2007 Physiological roles of STIM1 and Orai1 homologs and CRAC channels in the genetic model organism Caenorhabditis elegans. Cell calcium 21 17376526
2008 New therapeutic targets in immune disorders: ItpkB, Orai1 and UNC93B. Expert opinion on therapeutic targets 20 18348677
2021 ORAI1 Limits SARS-CoV-2 Infection by Regulating Tonic Type I IFN Signaling. Journal of immunology (Baltimore, Md. : 1950) 19 34819389
2023 Orai3 and Orai1 mediate CRAC channel function and metabolic reprogramming in B cells. eLife 18 36803766
2023 Orai1 is an Entotic Ca2+ Channel for Non-Apoptotic Cell Death, Entosis in Cancer Development. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 18 36960682
2021 S-acylation of Orai1 regulates store-operated Ca2+ entry. Journal of cell science 18 34156466
2021 Alteration of STIM1/Orai1-Mediated SOCE in Skeletal Muscle: Impact in Genetic Muscle Diseases and Beyond. Cells 18 34685702

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