{"gene":"ORAI1","run_date":"2026-06-10T05:19:53","timeline":{"discoveries":[{"year":2006,"finding":"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.","method":"Site-directed mutagenesis of conserved acidic residues in transmembrane segments combined with patch-clamp electrophysiology","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct mutagenesis of pore-lining residues with functional validation by electrophysiology; independently replicated by multiple labs (PMIDs 16978865, 16645049)","pmids":["16921383"],"is_preprint":false},{"year":2006,"finding":"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.","method":"Genome-wide RNAi screen in Drosophila cells followed by secondary patch-clamp screen; RNAi knockdown in human cells","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide screen plus electrophysiology; independently replicated across multiple labs","pmids":["16645049"],"is_preprint":false},{"year":2006,"finding":"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.","method":"Overexpression of STIM1 and CRACM1 in HEK293 cells combined with patch-clamp electrophysiology","journal":"Nature Cell Biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution experiment replicated independently by multiple groups (PMIDs 16766533, 16921383)","pmids":["16733527","16766533"],"is_preprint":false},{"year":2006,"finding":"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.","method":"Co-immunoprecipitation of CRACM1 multimers; site-directed mutagenesis combined with patch-clamp electrophysiology","journal":"Current Biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — mutagenesis + electrophysiology + Co-IP; multiple orthogonal methods in one study","pmids":["16978865"],"is_preprint":false},{"year":2006,"finding":"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.","method":"Ca2+ imaging and patch-clamp electrophysiology in HEK293 and RBL cells with individual and combined overexpression","journal":"Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution with both components; replicated across labs","pmids":["16766533"],"is_preprint":false},{"year":2007,"finding":"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.","method":"Patch-clamp electrophysiology; dominant-negative mutant cross-inhibition; pharmacological analysis in HEK293 cells stably expressing STIM1","journal":"Current Biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — electrophysiology with dominant-negative cross-inhibition; single lab but multiple orthogonal assays","pmids":["17442569"],"is_preprint":false},{"year":2007,"finding":"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.","method":"Gene-targeted Orai1-knockout mouse; mast cell degranulation assays; cytokine secretion; in vivo allergy models","journal":"Nature Immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean knockout mouse with specific cellular phenotype; multiple functional readouts","pmids":["18059270"],"is_preprint":false},{"year":2008,"finding":"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.","method":"Live-cell FRET microscopy between fluorescently tagged STIM1 and Orai1 or Orai1-Orai1 pairs; Orai1 mutant analysis","journal":"Journal of Physiology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — FRET with multiple mutant controls in live cells; single lab with two orthogonal measurements (STIM1-Orai1 and Orai1-Orai1 FRET)","pmids":["18832420"],"is_preprint":false},{"year":2008,"finding":"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.","method":"Confocal imaging; Ca2+ imaging with EGTA; dominant-negative Orai1 expression; co-localization with TCR and costimulatory molecules","journal":"PNAS","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct localization experiment with functional consequence; dominant-negative dissection of STIM1-Orai1 recruitment vs. gating","pmids":["18250319"],"is_preprint":false},{"year":2008,"finding":"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.","method":"Orai1-knockout mouse; Ca2+ imaging in platelets; flow chamber thrombus assays; pulmonary thromboembolism, arterial thrombosis, and stroke models in vivo","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean knockout mouse with multiple orthogonal functional readouts in vitro and in vivo","pmids":["18832659"],"is_preprint":false},{"year":2008,"finding":"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.","method":"FRET between STIM1-mRFP and AcGFP-Orai1; mutagenesis of cytoplasmic acidic residues; pharmacological inhibition with sphingosine derivatives; confocal microscopy","journal":"Molecular Biology of the Cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — FRET with mutagenesis; single lab, two methods","pmids":["18987344"],"is_preprint":false},{"year":2008,"finding":"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.","method":"Orai1 gene-targeted knockout mice; patch-clamp; Ca2+ imaging in T and B cells; proliferation assays","journal":"Molecular and Cellular Biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic knockout with electrophysiology and Ca2+ imaging; multiple immune cell types","pmids":["18591248"],"is_preprint":false},{"year":2009,"finding":"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.","method":"RNA silencing; Ca2+ imaging; patch-clamp electrophysiology; rescue by ectopic expression; cell cycle analysis by flow cytometry","journal":"Circulation Research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — knockdown plus rescue plus electrophysiology; multiple orthogonal methods","pmids":["18845811"],"is_preprint":false},{"year":2009,"finding":"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.","method":"RNAi knockdown; in vitro migration assays; in vivo tumor metastasis mouse models; pharmacological SOCE inhibition","journal":"Cancer Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — RNAi in vitro and in vivo; pharmacological validation; multiple orthogonal approaches","pmids":["19185847"],"is_preprint":false},{"year":2010,"finding":"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.","method":"siRNA knockdown of Orai1 in neonatal rat ventricular cardiomyocytes; Ca2+ imaging; phosphoprotein analysis; mRNA expression","journal":"Journal of Molecular and Cellular Cardiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with multiple downstream signaling readouts; single lab","pmids":["20138887"],"is_preprint":false},{"year":2011,"finding":"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.","method":"Heterologous expression of constitutively active/inactive SGK1 mutants; siRNA; SOCE measurement by Fura-2; patch-clamp; SGK1-knockout mast cells","journal":"FASEB Journal","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple genetic tools (active/inactive mutants, KO mice, siRNA) with electrophysiology and Ca2+ imaging; single lab but three orthogonal approaches","pmids":["21385992"],"is_preprint":false},{"year":2011,"finding":"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.","method":"Orai1-knockout mice; adoptive transfer; anti-CD3 injection; NFAT nuclear localization; ORAI1 mutant expression to titrate Ca2+ levels; flow cytometry","journal":"Journal of Immunology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean knockout plus rescue with constitutively active NFAT; in vivo and in vitro validation","pmids":["21873530"],"is_preprint":false},{"year":2011,"finding":"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.","method":"siRNA; dominant-negative Orai1; Ca2+ imaging; migration assay; tube formation assay; rescue by wild-type Orai1","journal":"Circulation Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockdown plus rescue; single lab, multiple functional readouts","pmids":["21441136"],"is_preprint":false},{"year":2013,"finding":"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.","method":"Orai1-knockout mice; primary keratinocytes; Ca2+ imaging; focal adhesion assays; pharmacological and genetic manipulation of PKCβ/Calpain/FAK","journal":"PNAS","confidence":"High","confidence_rationale":"Tier 2 / Moderate — knockout mouse with mechanistic pathway dissection (PKCβ-Calpain-FAK); multiple orthogonal methods","pmids":["24277812"],"is_preprint":false},{"year":2014,"finding":"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.","method":"STIM1 knockdown; Orai1 pharmacological blockade; live-cell imaging; invadopodium assays; MT1-MMP localization; Src activity assay; xenograft metastasis model","journal":"Journal of Cell Biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — mechanistic pathway dissection (Orai1→Ca2+ oscillations→Src→invadopodium; Orai1→MT1-MMP trafficking) with in vivo validation; single lab, multiple orthogonal methods","pmids":["25404747"],"is_preprint":false},{"year":2014,"finding":"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.","method":"Heterologous expression of patient mutations; patch-clamp electrophysiology measuring Ca2+-dependent inactivation; zebrafish model for STIM1 R304W","journal":"PNAS","confidence":"High","confidence_rationale":"Tier 1 / Moderate — electrophysiology with defined mutation plus in vivo zebrafish model; single lab but multiple orthogonal methods","pmids":["24591628"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Co-immunoprecipitation; overexpression of CSQ1 deletion mutants; Ca2+ imaging; SOCE measurement in HEK293 cells","journal":"Scientific Reports","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP plus Ca2+ imaging; single lab, two methods","pmids":["26087026"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Transmission and freeze-fracture electron microscopy of STIM1- and Orai1-transfected HEK293 cells with and without thapsigargin treatment","journal":"PNAS","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct structural visualization by EM at near-molecular resolution; single lab with rigorous controls","pmids":["26351694"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Orai1-knockout mice; in vitro osteoclast and osteoblast differentiation; Ca2+ imaging; resorption pit assay; bone densitometry","journal":"Cell Calcium","confidence":"High","confidence_rationale":"Tier 2 / Moderate — knockout mouse with mechanistically specific cellular phenotypes; multiple cell-type analysis","pmids":["23122304"],"is_preprint":false},{"year":2016,"finding":"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.","method":"Western blot; lectin-binding assays; Ca2+ imaging; patch-clamp; site-directed mutagenesis of N223; siRNA knockdown of ST6GAL1","journal":"Science Signaling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis plus knockdown plus electrophysiology; single lab, two orthogonal methods","pmids":["26956484"],"is_preprint":false},{"year":2016,"finding":"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.","method":"Ca2+ imaging; patch-clamp; PKC inhibition; expression of PKC-insensitive Orai1 mutant; fluorescence microscopy in patient-derived melanoma cells","journal":"Molecular and Cellular Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — PKC-insensitive mutant rescue; electrophysiology; single lab, two orthogonal methods","pmids":["26055321"],"is_preprint":false},{"year":2016,"finding":"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.","method":"siRNA knockdown; Ca2+ imaging; pharmacological inhibitors; adenoviral Orai1 siRNA in ApoE-/- mice; immunostaining","journal":"Arteriosclerosis Thrombosis and Vascular Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockdown with pathway dissection (calcineurin vs. ASK1/JNK/p38); in vivo validation; single lab","pmids":["26916730"],"is_preprint":false},{"year":2017,"finding":"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.","method":"Patch-clamp electrophysiology and Ca2+ imaging of mutant ORAI1 channels expressed in HEK cells; functional characterization with/without STIM1","journal":"Human Mutation","confidence":"High","confidence_rationale":"Tier 1 / Moderate — electrophysiology with multiple mutants and STIM1 dependence test; single lab with rigorous controls","pmids":["28058752"],"is_preprint":false},{"year":2017,"finding":"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.","method":"Biochemical binding assays; CaM-binding site mapping in STIM1; functional Ca2+ imaging and patch-clamp with wild-type and constitutively active STIM1 mutants","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — biochemical dissection of CaM-STIM1 interaction plus functional consequence on Orai1 inactivation; single lab, two orthogonal methods","pmids":["29051492"],"is_preprint":false},{"year":2018,"finding":"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.","method":"Concatenated SOAR heterodimers with point mutations; super-resolution microscopy; FRAP; Ca2+ oscillation measurements; co-expression experiments","journal":"PNAS","confidence":"High","confidence_rationale":"Tier 2 / Moderate — super-resolution imaging + FRAP + functional Ca2+ measurements + defined point mutants; single lab, multiple orthogonal methods","pmids":["29581306"],"is_preprint":false},{"year":2018,"finding":"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.","method":"Super-resolution microscopy; co-immunoprecipitation; FRET; NAADP signaling; knockout cell analysis; Ca2+ imaging","journal":"Science Signaling","confidence":"High","confidence_rationale":"Tier 2 / Moderate — super-resolution microscopy plus Co-IP/FRET plus knockout functional analysis; multiple orthogonal approaches","pmids":["30563862"],"is_preprint":false},{"year":2018,"finding":"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.","method":"Patch-clamp electrophysiology; Ca2+ imaging; molecular dynamics simulations; expression in Stim1-/-/Stim2-/- MEFs; primary human myoblasts","journal":"Journal of Physiology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — electrophysiology plus molecular dynamics plus knockout MEF reconstitution; single lab, multiple orthogonal methods","pmids":["30382595"],"is_preprint":false},{"year":2019,"finding":"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).","method":"Cysteine crosslinking; functional patch-clamp and Ca2+ imaging with STIM1 α3 mutants; proximity assay","journal":"Cell Calcium","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — crosslinking plus functional electrophysiology; single lab, two methods","pmids":["30831274"],"is_preprint":false},{"year":2019,"finding":"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.","method":"Super-resolution live-cell imaging of ORAI1, STIM1, and septin 4; co-localization analysis; STIM/septin perturbation","journal":"Scientific Reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — super-resolution imaging with defined genetic perturbations; single lab","pmids":["31346209"],"is_preprint":false},{"year":2019,"finding":"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.","method":"Co-immunoprecipitation; siRNA knockdown; Ca2+ imaging; ERK phosphorylation assay; cell migration assay; in vivo lung metastasis model","journal":"Cancer Science","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP (single) plus functional knockdown with pathway readout; single lab","pmids":["31755615"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Biochemical S-acylation detection (acyl-RAC); site-directed mutagenesis of C143; Ca2+ imaging; STIM1 puncta co-localization assay","journal":"Journal of Cell Science","confidence":"High","confidence_rationale":"Tier 1 / Moderate — biochemical detection of PTM plus mutagenesis plus functional Ca2+ entry assay plus localization; single lab, multiple orthogonal methods","pmids":["34156466"],"is_preprint":false},{"year":2016,"finding":"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.","method":"Oxidomimetic mutagenesis (C195D); SOCE measurement; single-particle tracking; molecular dynamics; experimental validation of intramolecular interaction","journal":"Scientific Reports","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — mutagenesis + molecular dynamics + functional assays; single lab, multiple orthogonal methods","pmids":["27624281"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Astrocyte-specific Orai1 knockout mice; transcriptomics; metabolomics; Ca2+ imaging; electrophysiology; behavioral tests","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific knockout with transcriptomic, metabolic, electrophysiological, and behavioral readouts; multiple orthogonal methods","pmids":["37679321"],"is_preprint":false},{"year":2013,"finding":"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.","method":"Co-immunoprecipitation of endogenous proteins; proximity ligation assay (PLA); Fura-2 Ca2+ imaging in cortical neurons","journal":"Journal of Neurochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus quantitative PLA plus Ca2+ imaging; single lab, two orthogonal interaction methods","pmids":["23711249"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Transcription factor binding assay (NF-κB promoter); SGK1 and AMPK gain/loss of function; Western blot; SOCE measurement","journal":"Cell Calcium","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — promoter binding plus kinase gain/loss-of-function; single lab, two methods","pmids":["22682960"],"is_preprint":false},{"year":2021,"finding":"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.","method":"ORAI1 and STIM1 CRISPR knockout in HEK293-ACE2 cells; transcriptome analysis; SARS-CoV-2 infection; ORAI1 blocker/agonist modulation; IFN-β expression assay","journal":"Journal of Immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout with transcriptomics and functional infection assay; single lab, two orthogonal approaches","pmids":["34819389"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Immunofluorescence localization; selective Orai1 inhibitor CM5480; Ca2+ imaging; in vitro secretion assays; in vivo acute pancreatitis models","journal":"Journal of Physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization plus pharmacological inhibition with in vitro and in vivo functional readouts; single lab","pmids":["35081662"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Ca2+ imaging with spatiotemporal analysis; SEPTIN/Orai1/MLCK inhibitors and knockdown; MLC phosphorylation assay; immunostaining","journal":"Advanced Science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological and genetic pathway dissection (SEPTIN→Orai1→CaM/MLCK→actomyosin); single lab, multiple readouts","pmids":["36960682"],"is_preprint":false},{"year":2015,"finding":"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.","method":"FRET; Ca2+ imaging; FRAP; TIRF microscopy; Western blot; in vivo inhalation model in wild-type and SPLUNC1-/- mice","journal":"American Journal of Respiratory Cell and Molecular Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — FRET for direct interaction plus in vivo functional validation; single lab, multiple orthogonal methods","pmids":["34807800"],"is_preprint":false}],"current_model":"ORAI1 (CRACM1/TMEM142A) is a plasma membrane, four-transmembrane-domain protein that forms homo- or heteromultimeric Ca2+-selective ion channels (the CRAC channel pore); conserved glutamate residues in TM1 (E106) and TM3 (E190) line the pore and determine ion selectivity; upon ER Ca2+ store depletion, the ER-resident sensor STIM1 oligomerizes, translocates to ER-PM junctions, physically binds the cytoplasmic C-terminus of Orai1 through its SOAR/CAD domain, and allosterically gates the channel open via a STIM1 α3–Orai1 TM3 gating interface; STIM1 dimers can cross-link multiple Orai1 channels to form clusters that enhance cooperativity; channel activity is negatively regulated by Ca2+-bound calmodulin disrupting the STIM1-Orai1 complex, by ROS-mediated intramolecular locking between oxidized C195 and S239, by N-glycosylation/sialic acid–Siglec interactions, and by protein kinase C-mediated phosphorylation; membrane Orai1 abundance is controlled by the SGK1/Nedd4-2 ubiquitin axis and NF-κB-driven transcription; S-acylation of C143 upon store depletion is required for Orai1 recruitment to ER-PM junctions; in immune cells (T cells, B cells, mast cells, neutrophils, platelets), Orai1-mediated Ca2+ entry activates NFAT to drive gene transcription, cytokine production, degranulation, and activation-induced cell death; in non-immune cells Orai1 regulates endothelial proliferation and tube formation, keratinocyte focal adhesion turnover via PKCβ-Calpain-FAK, cardiomyocyte hypertrophy via calcineurin/CaM KII/ERK, osteoclast fusion, and astrocyte reactivity."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":2006,"claim":"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","pmids":["16921383","16645049","16978865"],"confidence":"High","gaps":["Channel stoichiometry and the atomic architecture of the pore were not resolved","Mechanism by which the channel is gated open was unknown"]},{"year":2006,"claim":"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","pmids":["16733527","16766533","16978865"],"confidence":"High","gaps":["Whether STIM1-ORAI1 coupling was direct or indirect was not yet shown","Required stoichiometry between the two proteins was undefined"]},{"year":2007,"claim":"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","pmids":["17442569"],"confidence":"High","gaps":["Native heteromer composition in physiological cells not established","Functional consequences of paralog mixing in vivo unknown"]},{"year":2007,"claim":"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","pmids":["18059270"],"confidence":"High","gaps":["Downstream transcriptional program not dissected here","Cell-type-specific contributions not separable in global knockout"]},{"year":2008,"claim":"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","pmids":["18591248","18832659"],"confidence":"High","gaps":["Transcription factors coupling Ca2+ entry to phenotype not yet mapped","Tissue-specific versus developmental contributions not separated"]},{"year":2008,"claim":"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","pmids":["18832420","18250319","18987344"],"confidence":"High","gaps":["Molecular basis of the gating conformational change not resolved","Recruitment versus gating steps separable functionally but not yet structurally"]},{"year":2009,"claim":"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","pmids":["18845811","19185847"],"confidence":"High","gaps":["Downstream effectors linking Ca2+ entry to migration not fully defined at this stage","Specificity of SOCE pharmacology in vivo limited"]},{"year":2014,"claim":"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","pmids":["24591628"],"confidence":"High","gaps":["Tissue-level pathology in muscle not mechanistically connected to channel defect","Genotype-phenotype range incomplete"]},{"year":2018,"claim":"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","pmids":["29581306"],"confidence":"High","gaps":["Quantitative relationship between cluster size and current not fully defined","Physiological tuning of cross-linking in native cells unknown"]},{"year":2019,"claim":"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","pmids":["30831274"],"confidence":"Medium","gaps":["Crosslinking and electrophysiology from a single lab without structural confirmation","Allosteric pathway from interface to pore not resolved"]},{"year":2017,"claim":"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","pmids":["29051492","27624281"],"confidence":"Medium","gaps":["Redox findings rest on a single lab with oxidomimetic surrogates","Integration of multiple negative regulators in vivo not established"]},{"year":2021,"claim":"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","pmids":["34156466"],"confidence":"High","gaps":["Enzyme(s) catalyzing the S-acylation not identified","Kinetic relationship to STIM1 oligomerization not resolved"]},{"year":2023,"claim":"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","pmids":["37679321"],"confidence":"High","gaps":["Direct Ca2+-to-transcription effectors in astrocytes not fully mapped","Neuronal versus glial circuit contributions not separated"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified quantitative model of competing regulators","No high-resolution structure of the activated STIM1-ORAI1 gating complex in the timeline"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[0,1,3]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,7]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,22,41]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,7,16]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[6,11,16]},{"term_id":"R-HSA-109582","term_label":"Hemostasis","supporting_discovery_ids":[9]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[20,27,31]}],"complexes":["CRAC channel"],"partners":["STIM1","STIM2","ORAI2","ORAI3","RYR1","TRPC1","PTGER4","CALM1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96D31","full_name":"Calcium release-activated calcium channel protein 1","aliases":["Protein orai-1","Transmembrane protein 142A"],"length_aa":301,"mass_kda":32.7,"function":"Pore-forming subunit of two major inward rectifying Ca(2+) channels at the plasma membrane: Ca(2+) release-activated Ca(2+) (CRAC) channels and arachidonate-regulated Ca(2+)-selective (ARC) channels (Probable) (PubMed:16645049, PubMed:16733527, PubMed:16807233, PubMed:16921383, PubMed:19249086, PubMed:19706554, PubMed:23307288, PubMed:26956484, PubMed:28219928). Assembles with ORAI2 and ORAI3 to form hexameric CRAC channels that mediate Ca(2+) influx upon depletion of endoplasmic reticulum Ca(2+) store and channel activation by Ca(2+) sensor STIM1, a process known as store-operated Ca(2+) entry (SOCE). Various pore subunit combinations may account for distinct CRAC channel spatiotemporal and cell-type specific dynamics. ORAI1 mainly contributes to the generation of Ca(2+) plateaus involved in sustained Ca(2+) entry and is dispensable for cytosolic Ca(2+) oscillations, whereas ORAI2 and ORAI3 generate oscillatory patterns. CRAC channels assemble in Ca(2+) signaling microdomains where Ca(2+) influx is coupled to calmodulin and calcineurin signaling and activation of NFAT transcription factors recruited to ORAI1 via AKAP5. Activates NFATC2/NFAT1 and NFATC3/NFAT4-mediated transcriptional responses. CRAC channels are the main pathway for Ca(2+) influx in T cells and promote the immune response to pathogens by activating NFAT-dependent cytokine and chemokine transcription (PubMed:16582901, PubMed:17442569, PubMed:19182790, PubMed:20354224, PubMed:22641696, PubMed:26221052, PubMed:32415068, PubMed:33941685). Assembles with ORAI3 to form channels that mediate store-independent Ca(2+) influx in response to inflammatory metabolites arachidonate or its derivative leukotriene C4, termed ARC and LRC channels respectively (PubMed:19622606, PubMed:32415068). Plays a prominent role in Ca(2+) influx at the basolateral membrane of mammary epithelial cells independently of the Ca(2+) content of endoplasmic reticulum or Golgi stores. May mediate transepithelial transport of large quantities of Ca(2+) for milk secretion (By similarity) (PubMed:20887894) Pore-forming subunit of both CRAC and ARC channels. Couples Ca(2+) influx to NFAT-mediated transcriptional responses Pore-forming subunit of CRAC channels exclusively","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q96D31/entry"},"depmap":{"release":"DepMap","has_data":false,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ORAI1"},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000276045","cell_line_id":"CID000354","localizations":[{"compartment":"membrane","grade":3},{"compartment":"er","grade":2}],"interactors":[{"gene":"UBE3B","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000354","total_profiled":1310},"omim":[{"mim_id":"619863","title":"JUNCTOPHILIN 4; JPH4","url":"https://www.omim.org/entry/619863"},{"mim_id":"619399","title":"TETRASPANIN 18; TSPAN18","url":"https://www.omim.org/entry/619399"},{"mim_id":"617167","title":"SOLUTE CARRIER FAMILY 35, MEMBER G1; SLC35G1","url":"https://www.omim.org/entry/617167"},{"mim_id":"615883","title":"MYOPATHY, TUBULAR AGGREGATE, 2; TAM2","url":"https://www.omim.org/entry/615883"},{"mim_id":"614768","title":"TRANSMEMBRANE PROTEIN 66; TMEM66","url":"https://www.omim.org/entry/614768"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"choroid plexus","ntpm":63.1},{"tissue":"skeletal muscle","ntpm":57.2}],"url":"https://www.proteinatlas.org/search/ORAI1"},"hgnc":{"alias_symbol":["FLJ14466","CRACM1"],"prev_symbol":["TMEM142A"]},"alphafold":{"accession":"Q96D31","domains":[{"cath_id":"1.20.140.140","chopping":"113-201_230-284","consensus_level":"medium","plddt":82.0051,"start":113,"end":284}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96D31","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96D31-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96D31-F1-predicted_aligned_error_v6.png","plddt_mean":71.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ORAI1","jax_strain_url":"https://www.jax.org/strain/search?query=ORAI1"},"sequence":{"accession":"Q96D31","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96D31.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96D31/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96D31"}},"corpus_meta":[{"pmid":"16921383","id":"PMC_16921383","title":"Orai1 is an essential pore subunit of the CRAC channel.","date":"2006","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/16921383","citation_count":1141,"is_preprint":false},{"pmid":"16645049","id":"PMC_16645049","title":"CRACM1 is a plasma membrane protein essential for store-operated Ca2+ entry.","date":"2006","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/16645049","citation_count":1138,"is_preprint":false},{"pmid":"19185847","id":"PMC_19185847","title":"Orai1 and STIM1 are critical for breast tumor cell migration and metastasis.","date":"2009","source":"Cancer cell","url":"https://pubmed.ncbi.nlm.nih.gov/19185847","citation_count":574,"is_preprint":false},{"pmid":"16733527","id":"PMC_16733527","title":"Amplification of CRAC current by STIM1 and CRACM1 (Orai1).","date":"2006","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/16733527","citation_count":484,"is_preprint":false},{"pmid":"16978865","id":"PMC_16978865","title":"CRACM1 multimers form the ion-selective pore of the CRAC channel.","date":"2006","source":"Current biology : CB","url":"https://pubmed.ncbi.nlm.nih.gov/16978865","citation_count":481,"is_preprint":false},{"pmid":"16766533","id":"PMC_16766533","title":"Orai1 and STIM reconstitute store-operated calcium channel function.","date":"2006","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16766533","citation_count":464,"is_preprint":false},{"pmid":"26469693","id":"PMC_26469693","title":"Diseases caused by mutations in ORAI1 and STIM1.","date":"2015","source":"Annals of the New York Academy of Sciences","url":"https://pubmed.ncbi.nlm.nih.gov/26469693","citation_count":374,"is_preprint":false},{"pmid":"18059270","id":"PMC_18059270","title":"Defective mast cell effector functions in mice lacking the CRACM1 pore subunit of store-operated calcium release-activated calcium channels.","date":"2007","source":"Nature immunology","url":"https://pubmed.ncbi.nlm.nih.gov/18059270","citation_count":342,"is_preprint":false},{"pmid":"18845811","id":"PMC_18845811","title":"Stim1 and Orai1 mediate CRAC currents and store-operated calcium entry important for endothelial cell proliferation.","date":"2008","source":"Circulation research","url":"https://pubmed.ncbi.nlm.nih.gov/18845811","citation_count":326,"is_preprint":false},{"pmid":"17442569","id":"PMC_17442569","title":"CRACM1, CRACM2, and CRACM3 are store-operated Ca2+ channels with distinct functional properties.","date":"2007","source":"Current biology : CB","url":"https://pubmed.ncbi.nlm.nih.gov/17442569","citation_count":315,"is_preprint":false},{"pmid":"20004786","id":"PMC_20004786","title":"ORAI1 deficiency and lack of store-operated Ca2+ entry cause immunodeficiency, myopathy, and ectodermal dysplasia.","date":"2009","source":"The Journal of allergy and clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/20004786","citation_count":274,"is_preprint":false},{"pmid":"18591248","id":"PMC_18591248","title":"Hair loss and defective T- and B-cell function in mice lacking ORAI1.","date":"2008","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/18591248","citation_count":254,"is_preprint":false},{"pmid":"18832659","id":"PMC_18832659","title":"Orai1 (CRACM1) is the platelet SOC channel and essential for pathological thrombus formation.","date":"2008","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/18832659","citation_count":232,"is_preprint":false},{"pmid":"18250319","id":"PMC_18250319","title":"Orai1 and STIM1 move to the immunological synapse and are up-regulated during T cell activation.","date":"2008","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/18250319","citation_count":223,"is_preprint":false},{"pmid":"24591628","id":"PMC_24591628","title":"Activating mutations in STIM1 and ORAI1 cause overlapping syndromes of tubular myopathy and congenital miosis.","date":"2014","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/24591628","citation_count":210,"is_preprint":false},{"pmid":"28089266","id":"PMC_28089266","title":"TRPC1, Orai1, and STIM1 in SOCE: Friends in tight spaces.","date":"2016","source":"Cell calcium","url":"https://pubmed.ncbi.nlm.nih.gov/28089266","citation_count":187,"is_preprint":false},{"pmid":"18832420","id":"PMC_18832420","title":"STIM1-Orai1 interactions and Orai1 conformational changes revealed by live-cell FRET microscopy.","date":"2008","source":"The Journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/18832420","citation_count":184,"is_preprint":false},{"pmid":"21441136","id":"PMC_21441136","title":"Orai1 and CRAC channel dependence of VEGF-activated Ca2+ entry and endothelial tube formation.","date":"2011","source":"Circulation research","url":"https://pubmed.ncbi.nlm.nih.gov/21441136","citation_count":172,"is_preprint":false},{"pmid":"23515871","id":"PMC_23515871","title":"STIM1 and Orai1 mediate CRAC channel activity and are essential for human glioblastoma invasion.","date":"2013","source":"Pflugers Archiv : European journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/23515871","citation_count":164,"is_preprint":false},{"pmid":"20189884","id":"PMC_20189884","title":"Immunodeficiency due to mutations in ORAI1 and STIM1.","date":"2010","source":"Clinical immunology (Orlando, Fla.)","url":"https://pubmed.ncbi.nlm.nih.gov/20189884","citation_count":146,"is_preprint":false},{"pmid":"25404747","id":"PMC_25404747","title":"STIM1- and Orai1-mediated Ca(2+) oscillation orchestrates invadopodium formation and melanoma invasion.","date":"2014","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/25404747","citation_count":139,"is_preprint":false},{"pmid":"20138887","id":"PMC_20138887","title":"Orai1 and Stim1 regulate normal and hypertrophic growth in cardiomyocytes.","date":"2010","source":"Journal of molecular and cellular cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/20138887","citation_count":130,"is_preprint":false},{"pmid":"24797725","id":"PMC_24797725","title":"Elevated Orai1 expression mediates tumor-promoting intracellular Ca2+ oscillations in human esophageal squamous cell carcinoma.","date":"2014","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/24797725","citation_count":129,"is_preprint":false},{"pmid":"18987344","id":"PMC_18987344","title":"Molecular clustering of STIM1 with Orai1/CRACM1 at the plasma membrane depends dynamically on depletion of Ca2+ stores and on electrostatic interactions.","date":"2008","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/18987344","citation_count":122,"is_preprint":false},{"pmid":"19944100","id":"PMC_19944100","title":"An endoplasmic reticulum/plasma membrane junction: STIM1/Orai1/TRPCs.","date":"2009","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/19944100","citation_count":112,"is_preprint":false},{"pmid":"23792674","id":"PMC_23792674","title":"STIM1/Orai1-mediated SOCE: current perspectives and potential roles in cardiac function and pathology.","date":"2013","source":"American journal of physiology. Heart and circulatory physiology","url":"https://pubmed.ncbi.nlm.nih.gov/23792674","citation_count":111,"is_preprint":false},{"pmid":"37679321","id":"PMC_37679321","title":"Astrocyte reactivity and inflammation-induced depression-like behaviors are regulated by Orai1 calcium channels.","date":"2023","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/37679321","citation_count":107,"is_preprint":false},{"pmid":"24583265","id":"PMC_24583265","title":"Orai1 and STIM1 mediate SOCE and contribute to apoptotic resistance of pancreatic adenocarcinoma.","date":"2014","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/24583265","citation_count":103,"is_preprint":false},{"pmid":"21945734","id":"PMC_21945734","title":"Calcium entry via ORAI1 regulates glioblastoma cell proliferation and apoptosis.","date":"2011","source":"Experimental and molecular pathology","url":"https://pubmed.ncbi.nlm.nih.gov/21945734","citation_count":94,"is_preprint":false},{"pmid":"28058752","id":"PMC_28058752","title":"ORAI1 Mutations with Distinct Channel Gating Defects in Tubular Aggregate Myopathy.","date":"2017","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/28058752","citation_count":91,"is_preprint":false},{"pmid":"30530091","id":"PMC_30530091","title":"STIM1 activation of Orai1.","date":"2018","source":"Cell calcium","url":"https://pubmed.ncbi.nlm.nih.gov/30530091","citation_count":87,"is_preprint":false},{"pmid":"26215475","id":"PMC_26215475","title":"The STIM1-ORAI1 microdomain.","date":"2015","source":"Cell calcium","url":"https://pubmed.ncbi.nlm.nih.gov/26215475","citation_count":86,"is_preprint":false},{"pmid":"21385992","id":"PMC_21385992","title":"Stimulation of Ca2+-channel Orai1/STIM1 by serum- and glucocorticoid-inducible kinase 1 (SGK1).","date":"2011","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/21385992","citation_count":83,"is_preprint":false},{"pmid":"23483280","id":"PMC_23483280","title":"Orai1-NFAT signalling pathway triggered by T cell receptor stimulation.","date":"2013","source":"Molecules and cells","url":"https://pubmed.ncbi.nlm.nih.gov/23483280","citation_count":82,"is_preprint":false},{"pmid":"26916730","id":"PMC_26916730","title":"Inhibition of Orai1 Store-Operated Calcium Channel Prevents Foam Cell Formation and Atherosclerosis.","date":"2016","source":"Arteriosclerosis, thrombosis, and vascular biology","url":"https://pubmed.ncbi.nlm.nih.gov/26916730","citation_count":76,"is_preprint":false},{"pmid":"25471906","id":"PMC_25471906","title":"STIM1, STIM2, and Orai1 regulate store-operated calcium entry and purinergic activation of microglia.","date":"2014","source":"Glia","url":"https://pubmed.ncbi.nlm.nih.gov/25471906","citation_count":76,"is_preprint":false},{"pmid":"21290310","id":"PMC_21290310","title":"Contribution of TRPC1 and Orai1 to Ca(2+) entry activated by store depletion.","date":"2011","source":"Advances in experimental medicine and biology","url":"https://pubmed.ncbi.nlm.nih.gov/21290310","citation_count":75,"is_preprint":false},{"pmid":"21873530","id":"PMC_21873530","title":"ORAI1 deficiency impairs activated T cell death and enhances T cell survival.","date":"2011","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/21873530","citation_count":70,"is_preprint":false},{"pmid":"36164973","id":"PMC_36164973","title":"Orai1 Inhibitors as Potential Treatments for Pulmonary Arterial Hypertension.","date":"2022","source":"Circulation research","url":"https://pubmed.ncbi.nlm.nih.gov/36164973","citation_count":67,"is_preprint":false},{"pmid":"30563862","id":"PMC_30563862","title":"ORAI1, STIM1/2, and RYR1 shape subsecond Ca2+ microdomains upon T cell activation.","date":"2018","source":"Science signaling","url":"https://pubmed.ncbi.nlm.nih.gov/30563862","citation_count":66,"is_preprint":false},{"pmid":"29634917","id":"PMC_29634917","title":"Ca2+ handling remodeling and STIM1L/Orai1/TRPC1/TRPC4 upregulation in monocrotaline-induced right ventricular hypertrophy.","date":"2018","source":"Journal of molecular and cellular cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/29634917","citation_count":65,"is_preprint":false},{"pmid":"28087079","id":"PMC_28087079","title":"The STIM-Orai coupling interface and gating of the Orai1 channel.","date":"2017","source":"Cell calcium","url":"https://pubmed.ncbi.nlm.nih.gov/28087079","citation_count":63,"is_preprint":false},{"pmid":"24277812","id":"PMC_24277812","title":"ORAI1 calcium channel orchestrates skin homeostasis.","date":"2013","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/24277812","citation_count":63,"is_preprint":false},{"pmid":"22682960","id":"PMC_22682960","title":"Regulation of Orai1/STIM1 by the kinases SGK1 and AMPK.","date":"2012","source":"Cell calcium","url":"https://pubmed.ncbi.nlm.nih.gov/22682960","citation_count":60,"is_preprint":false},{"pmid":"21782006","id":"PMC_21782006","title":"Orai1/CRACM1 overexpression suppresses cell proliferation via attenuation of the store-operated calcium influx-mediated signalling pathway in A549 lung cancer cells.","date":"2011","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/21782006","citation_count":58,"is_preprint":false},{"pmid":"31906693","id":"PMC_31906693","title":"Orai1 Channel Inhibition Preserves Left Ventricular Systolic Function and Normal Ca2+ Handling After Pressure Overload.","date":"2020","source":"Circulation","url":"https://pubmed.ncbi.nlm.nih.gov/31906693","citation_count":57,"is_preprint":false},{"pmid":"29581306","id":"PMC_29581306","title":"Cross-linking of Orai1 channels by STIM proteins.","date":"2018","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/29581306","citation_count":56,"is_preprint":false},{"pmid":"30950063","id":"PMC_30950063","title":"Molecular basis of allosteric Orai1 channel activation by STIM1.","date":"2019","source":"The Journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/30950063","citation_count":55,"is_preprint":false},{"pmid":"23846758","id":"PMC_23846758","title":"Regulation of STIM1/Orai1-dependent Ca2+ signalling in platelets.","date":"2013","source":"Thrombosis and haemostasis","url":"https://pubmed.ncbi.nlm.nih.gov/23846758","citation_count":54,"is_preprint":false},{"pmid":"22402985","id":"PMC_22402985","title":"Orai1 calcium channels in the vasculature.","date":"2012","source":"Pflugers Archiv : European journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/22402985","citation_count":53,"is_preprint":false},{"pmid":"23711249","id":"PMC_23711249","title":"Native STIM2 and ORAI1 proteins form a calcium-sensitive and thapsigargin-insensitive complex in cortical neurons.","date":"2013","source":"Journal of neurochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23711249","citation_count":53,"is_preprint":false},{"pmid":"31415242","id":"PMC_31415242","title":"Calcium channel Orai1 promotes lymphocyte IL-17 expression and progressive kidney injury.","date":"2019","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/31415242","citation_count":51,"is_preprint":false},{"pmid":"26351694","id":"PMC_26351694","title":"Nanoscale patterning of STIM1 and Orai1 during store-operated Ca2+ entry.","date":"2015","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/26351694","citation_count":51,"is_preprint":false},{"pmid":"26631141","id":"PMC_26631141","title":"NFκB-sensitive Orai1 expression in the regulation of FGF23 release.","date":"2015","source":"Journal of molecular medicine (Berlin, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/26631141","citation_count":48,"is_preprint":false},{"pmid":"27245842","id":"PMC_27245842","title":"STIMs and Orai1 regulate cytokine production in spinal astrocytes.","date":"2016","source":"Journal of neuroinflammation","url":"https://pubmed.ncbi.nlm.nih.gov/27245842","citation_count":47,"is_preprint":false},{"pmid":"27865925","id":"PMC_27865925","title":"Orai1 and Orai2 mediate store-operated calcium entry that regulates HL60 cell migration and FAK phosphorylation.","date":"2016","source":"Biochimica et biophysica acta. Molecular cell research","url":"https://pubmed.ncbi.nlm.nih.gov/27865925","citation_count":47,"is_preprint":false},{"pmid":"26087026","id":"PMC_26087026","title":"Retrograde regulation of STIM1-Orai1 interaction and store-operated Ca2+ entry by calsequestrin.","date":"2015","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/26087026","citation_count":47,"is_preprint":false},{"pmid":"25805497","id":"PMC_25805497","title":"STIM1/ORAI1-mediated Ca2+ Influx Regulates Enolase-1 Exteriorization.","date":"2015","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25805497","citation_count":46,"is_preprint":false},{"pmid":"25843208","id":"PMC_25843208","title":"The ER/PM microdomain, PI(4,5)P₂ and the regulation of STIM1-Orai1 channel function.","date":"2015","source":"Cell calcium","url":"https://pubmed.ncbi.nlm.nih.gov/25843208","citation_count":46,"is_preprint":false},{"pmid":"29051492","id":"PMC_29051492","title":"Calmodulin dissociates the STIM1-Orai1 complex and STIM1 oligomers.","date":"2017","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/29051492","citation_count":46,"is_preprint":false},{"pmid":"30831274","id":"PMC_30831274","title":"A novel STIM1-Orai1 gating interface essential for CRAC channel activation.","date":"2019","source":"Cell calcium","url":"https://pubmed.ncbi.nlm.nih.gov/30831274","citation_count":45,"is_preprint":false},{"pmid":"26789410","id":"PMC_26789410","title":"Variations in ORAI1 Gene Associated with Kawasaki Disease.","date":"2016","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/26789410","citation_count":45,"is_preprint":false},{"pmid":"26055321","id":"PMC_26055321","title":"Novel Protein Kinase C-Mediated Control of Orai1 Function in Invasive Melanoma.","date":"2015","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/26055321","citation_count":44,"is_preprint":false},{"pmid":"26793113","id":"PMC_26793113","title":"STIM and Orai1 Variants in Store-Operated Calcium Entry.","date":"2016","source":"Frontiers in pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/26793113","citation_count":42,"is_preprint":false},{"pmid":"23122304","id":"PMC_23122304","title":"Deletion of Orai1 alters expression of multiple genes during osteoclast and osteoblast maturation.","date":"2012","source":"Cell calcium","url":"https://pubmed.ncbi.nlm.nih.gov/23122304","citation_count":42,"is_preprint":false},{"pmid":"32929002","id":"PMC_32929002","title":"ORAI1 and ORAI2 modulate murine neutrophil calcium signaling, cellular activation, and host defense.","date":"2020","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/32929002","citation_count":41,"is_preprint":false},{"pmid":"26956484","id":"PMC_26956484","title":"Cell type-specific glycosylation of Orai1 modulates store-operated Ca2+ entry.","date":"2016","source":"Science signaling","url":"https://pubmed.ncbi.nlm.nih.gov/26956484","citation_count":37,"is_preprint":false},{"pmid":"30382595","id":"PMC_30382595","title":"ORAI1 channel gating and selectivity is differentially altered by natural mutations in the first or third transmembrane domain.","date":"2018","source":"The Journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/30382595","citation_count":37,"is_preprint":false},{"pmid":"25912155","id":"PMC_25912155","title":"Orai1 controls C5a-induced neutrophil recruitment in inflammation.","date":"2015","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/25912155","citation_count":36,"is_preprint":false},{"pmid":"31203007","id":"PMC_31203007","title":"TRPC1 and ORAI1 channels in colon cancer.","date":"2019","source":"Cell calcium","url":"https://pubmed.ncbi.nlm.nih.gov/31203007","citation_count":34,"is_preprint":false},{"pmid":"27624281","id":"PMC_27624281","title":"Thiol dependent intramolecular locking of Orai1 channels.","date":"2016","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/27624281","citation_count":33,"is_preprint":false},{"pmid":"29753044","id":"PMC_29753044","title":"Hypoxia-induced upregulation of Orai1 drives colon cancer invasiveness and angiogenesis.","date":"2018","source":"European journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/29753044","citation_count":32,"is_preprint":false},{"pmid":"31346209","id":"PMC_31346209","title":"Septins organize endoplasmic reticulum-plasma membrane junctions for STIM1-ORAI1 calcium signalling.","date":"2019","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/31346209","citation_count":31,"is_preprint":false},{"pmid":"23890113","id":"PMC_23890113","title":"Alternative forms of the store-operated calcium entry mediators, STIM1 and Orai1.","date":"2013","source":"Current topics in membranes","url":"https://pubmed.ncbi.nlm.nih.gov/23890113","citation_count":30,"is_preprint":false},{"pmid":"30921687","id":"PMC_30921687","title":"Store-independent Orai1-mediated Ca2+ entry and cancer.","date":"2019","source":"Cell calcium","url":"https://pubmed.ncbi.nlm.nih.gov/30921687","citation_count":29,"is_preprint":false},{"pmid":"18711860","id":"PMC_18711860","title":"Store-operated Orai1 and IP3 receptor-operated TRPC1 channel.","date":"2007","source":"Channels (Austin, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/18711860","citation_count":29,"is_preprint":false},{"pmid":"20194530","id":"PMC_20194530","title":"Expression and association of TRPC subtypes with Orai1 and STIM1 in human parathyroid.","date":"2010","source":"Journal of molecular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/20194530","citation_count":29,"is_preprint":false},{"pmid":"28743945","id":"PMC_28743945","title":"Lithium Sensitive ORAI1 Expression, Store Operated Ca2+ Entry and Suicidal Death of Neurons in Chorea-Acanthocytosis.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/28743945","citation_count":28,"is_preprint":false},{"pmid":"28258822","id":"PMC_28258822","title":"Intra-articular lentivirus-mediated gene therapy targeting CRACM1 for the treatment of collagen-induced arthritis.","date":"2017","source":"Journal of pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/28258822","citation_count":27,"is_preprint":false},{"pmid":"35081662","id":"PMC_35081662","title":"Bile acid- and ethanol-mediated activation of Orai1 damages pancreatic ductal secretion in acute pancreatitis.","date":"2022","source":"The Journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/35081662","citation_count":27,"is_preprint":false},{"pmid":"24321771","id":"PMC_24321771","title":"Are Orai1 and Orai3 channels more important than calcium influx for cell proliferation?","date":"2013","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/24321771","citation_count":27,"is_preprint":false},{"pmid":"26177720","id":"PMC_26177720","title":"Orai/CRACM1 and KCa3.1 ion channels interact in the human lung mast cell plasma membrane.","date":"2015","source":"Cell communication and signaling : CCS","url":"https://pubmed.ncbi.nlm.nih.gov/26177720","citation_count":26,"is_preprint":false},{"pmid":"31755615","id":"PMC_31755615","title":"Prostaglandin E2 receptor EP4 regulates cell migration through Orai1.","date":"2019","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/31755615","citation_count":26,"is_preprint":false},{"pmid":"33748129","id":"PMC_33748129","title":"SARAF and Orai1 Contribute to Endothelial Cell Activation and Angiogenesis.","date":"2021","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/33748129","citation_count":25,"is_preprint":false},{"pmid":"37227782","id":"PMC_37227782","title":"Orai1 calcium channel inhibition prevents progression of chronic pancreatitis.","date":"2023","source":"JCI insight","url":"https://pubmed.ncbi.nlm.nih.gov/37227782","citation_count":24,"is_preprint":false},{"pmid":"34807800","id":"PMC_34807800","title":"A SPLUNC1 Peptidomimetic Inhibits Orai1 and Reduces Inflammation in a Murine Allergic Asthma Model.","date":"2022","source":"American journal of respiratory cell and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/34807800","citation_count":23,"is_preprint":false},{"pmid":"23800047","id":"PMC_23800047","title":"Involvement of STIM1 and Orai1 in EGF-mediated cell growth in retinal pigment epithelial cells.","date":"2013","source":"Journal of biomedical science","url":"https://pubmed.ncbi.nlm.nih.gov/23800047","citation_count":23,"is_preprint":false},{"pmid":"24043696","id":"PMC_24043696","title":"TGFβ1 and SGK1-sensitive store-operated Ca2+ entry and Orai1 expression in endometrial Ishikawa cells.","date":"2013","source":"Molecular human reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/24043696","citation_count":23,"is_preprint":false},{"pmid":"21786201","id":"PMC_21786201","title":"STIM1 and Orai1: novel targets for vascular diseases?","date":"2011","source":"Science China. Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/21786201","citation_count":22,"is_preprint":false},{"pmid":"31366337","id":"PMC_31366337","title":"Functional consequences of enhanced expression of STIM1 and Orai1 in Huh-7 hepatocellular carcinoma tumor-initiating cells.","date":"2019","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/31366337","citation_count":22,"is_preprint":false},{"pmid":"28446591","id":"PMC_28446591","title":"NFAT5-sensitive Orai1 expression and store-operated Ca2+ entry in megakaryocytes.","date":"2017","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/28446591","citation_count":21,"is_preprint":false},{"pmid":"27960157","id":"PMC_27960157","title":"Chorein Sensitive Orai1 Expression and Store Operated Ca2+ Entry in Rhabdomyosarcoma Cells.","date":"2016","source":"Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/27960157","citation_count":21,"is_preprint":false},{"pmid":"30408546","id":"PMC_30408546","title":"STIM1 and Orai1 regulate Ca2+ microdomains for activation of transcription.","date":"2018","source":"Biochimica et biophysica acta. Molecular cell research","url":"https://pubmed.ncbi.nlm.nih.gov/30408546","citation_count":21,"is_preprint":false},{"pmid":"17376526","id":"PMC_17376526","title":"Physiological roles of STIM1 and Orai1 homologs and CRAC channels in the genetic model organism Caenorhabditis elegans.","date":"2007","source":"Cell calcium","url":"https://pubmed.ncbi.nlm.nih.gov/17376526","citation_count":21,"is_preprint":false},{"pmid":"18348677","id":"PMC_18348677","title":"New therapeutic targets in immune disorders: ItpkB, Orai1 and UNC93B.","date":"2008","source":"Expert opinion on therapeutic targets","url":"https://pubmed.ncbi.nlm.nih.gov/18348677","citation_count":20,"is_preprint":false},{"pmid":"34819389","id":"PMC_34819389","title":"ORAI1 Limits SARS-CoV-2 Infection by Regulating Tonic Type I IFN Signaling.","date":"2021","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/34819389","citation_count":19,"is_preprint":false},{"pmid":"34156466","id":"PMC_34156466","title":"S-acylation of Orai1 regulates store-operated Ca2+ entry.","date":"2021","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/34156466","citation_count":18,"is_preprint":false},{"pmid":"36803766","id":"PMC_36803766","title":"Orai3 and Orai1 mediate CRAC channel function and metabolic reprogramming in B cells.","date":"2023","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/36803766","citation_count":18,"is_preprint":false},{"pmid":"36960682","id":"PMC_36960682","title":"Orai1 is an Entotic Ca2+ Channel for Non-Apoptotic Cell Death, Entosis in Cancer Development.","date":"2023","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/36960682","citation_count":18,"is_preprint":false},{"pmid":"34685702","id":"PMC_34685702","title":"Alteration of STIM1/Orai1-Mediated SOCE in Skeletal Muscle: Impact in Genetic Muscle Diseases and Beyond.","date":"2021","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/34685702","citation_count":18,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":53051,"output_tokens":11142,"usd":0.163141,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":21957,"output_tokens":4416,"usd":0.110092,"stage2_stop_reason":"end_turn"},"total_usd":0.273233,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2006,\n      \"finding\": \"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.\",\n      \"method\": \"Site-directed mutagenesis of conserved acidic residues in transmembrane segments combined with patch-clamp electrophysiology\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct mutagenesis of pore-lining residues with functional validation by electrophysiology; independently replicated by multiple labs (PMIDs 16978865, 16645049)\",\n      \"pmids\": [\"16921383\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"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.\",\n      \"method\": \"Genome-wide RNAi screen in Drosophila cells followed by secondary patch-clamp screen; RNAi knockdown in human cells\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide screen plus electrophysiology; independently replicated across multiple labs\",\n      \"pmids\": [\"16645049\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"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.\",\n      \"method\": \"Overexpression of STIM1 and CRACM1 in HEK293 cells combined with patch-clamp electrophysiology\",\n      \"journal\": \"Nature Cell Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution experiment replicated independently by multiple groups (PMIDs 16766533, 16921383)\",\n      \"pmids\": [\"16733527\", \"16766533\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation of CRACM1 multimers; site-directed mutagenesis combined with patch-clamp electrophysiology\",\n      \"journal\": \"Current Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mutagenesis + electrophysiology + Co-IP; multiple orthogonal methods in one study\",\n      \"pmids\": [\"16978865\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"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.\",\n      \"method\": \"Ca2+ imaging and patch-clamp electrophysiology in HEK293 and RBL cells with individual and combined overexpression\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution with both components; replicated across labs\",\n      \"pmids\": [\"16766533\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"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.\",\n      \"method\": \"Patch-clamp electrophysiology; dominant-negative mutant cross-inhibition; pharmacological analysis in HEK293 cells stably expressing STIM1\",\n      \"journal\": \"Current Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — electrophysiology with dominant-negative cross-inhibition; single lab but multiple orthogonal assays\",\n      \"pmids\": [\"17442569\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"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.\",\n      \"method\": \"Gene-targeted Orai1-knockout mouse; mast cell degranulation assays; cytokine secretion; in vivo allergy models\",\n      \"journal\": \"Nature Immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean knockout mouse with specific cellular phenotype; multiple functional readouts\",\n      \"pmids\": [\"18059270\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"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.\",\n      \"method\": \"Live-cell FRET microscopy between fluorescently tagged STIM1 and Orai1 or Orai1-Orai1 pairs; Orai1 mutant analysis\",\n      \"journal\": \"Journal of Physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — FRET with multiple mutant controls in live cells; single lab with two orthogonal measurements (STIM1-Orai1 and Orai1-Orai1 FRET)\",\n      \"pmids\": [\"18832420\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"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.\",\n      \"method\": \"Confocal imaging; Ca2+ imaging with EGTA; dominant-negative Orai1 expression; co-localization with TCR and costimulatory molecules\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiment with functional consequence; dominant-negative dissection of STIM1-Orai1 recruitment vs. gating\",\n      \"pmids\": [\"18250319\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"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.\",\n      \"method\": \"Orai1-knockout mouse; Ca2+ imaging in platelets; flow chamber thrombus assays; pulmonary thromboembolism, arterial thrombosis, and stroke models in vivo\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean knockout mouse with multiple orthogonal functional readouts in vitro and in vivo\",\n      \"pmids\": [\"18832659\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"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.\",\n      \"method\": \"FRET between STIM1-mRFP and AcGFP-Orai1; mutagenesis of cytoplasmic acidic residues; pharmacological inhibition with sphingosine derivatives; confocal microscopy\",\n      \"journal\": \"Molecular Biology of the Cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — FRET with mutagenesis; single lab, two methods\",\n      \"pmids\": [\"18987344\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"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.\",\n      \"method\": \"Orai1 gene-targeted knockout mice; patch-clamp; Ca2+ imaging in T and B cells; proliferation assays\",\n      \"journal\": \"Molecular and Cellular Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic knockout with electrophysiology and Ca2+ imaging; multiple immune cell types\",\n      \"pmids\": [\"18591248\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"RNA silencing; Ca2+ imaging; patch-clamp electrophysiology; rescue by ectopic expression; cell cycle analysis by flow cytometry\",\n      \"journal\": \"Circulation Research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockdown plus rescue plus electrophysiology; multiple orthogonal methods\",\n      \"pmids\": [\"18845811\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"RNAi knockdown; in vitro migration assays; in vivo tumor metastasis mouse models; pharmacological SOCE inhibition\",\n      \"journal\": \"Cancer Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — RNAi in vitro and in vivo; pharmacological validation; multiple orthogonal approaches\",\n      \"pmids\": [\"19185847\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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.\",\n      \"method\": \"siRNA knockdown of Orai1 in neonatal rat ventricular cardiomyocytes; Ca2+ imaging; phosphoprotein analysis; mRNA expression\",\n      \"journal\": \"Journal of Molecular and Cellular Cardiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with multiple downstream signaling readouts; single lab\",\n      \"pmids\": [\"20138887\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"Heterologous expression of constitutively active/inactive SGK1 mutants; siRNA; SOCE measurement by Fura-2; patch-clamp; SGK1-knockout mast cells\",\n      \"journal\": \"FASEB Journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple genetic tools (active/inactive mutants, KO mice, siRNA) with electrophysiology and Ca2+ imaging; single lab but three orthogonal approaches\",\n      \"pmids\": [\"21385992\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"Orai1-knockout mice; adoptive transfer; anti-CD3 injection; NFAT nuclear localization; ORAI1 mutant expression to titrate Ca2+ levels; flow cytometry\",\n      \"journal\": \"Journal of Immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean knockout plus rescue with constitutively active NFAT; in vivo and in vitro validation\",\n      \"pmids\": [\"21873530\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"siRNA; dominant-negative Orai1; Ca2+ imaging; migration assay; tube formation assay; rescue by wild-type Orai1\",\n      \"journal\": \"Circulation Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockdown plus rescue; single lab, multiple functional readouts\",\n      \"pmids\": [\"21441136\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"Orai1-knockout mice; primary keratinocytes; Ca2+ imaging; focal adhesion assays; pharmacological and genetic manipulation of PKCβ/Calpain/FAK\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockout mouse with mechanistic pathway dissection (PKCβ-Calpain-FAK); multiple orthogonal methods\",\n      \"pmids\": [\"24277812\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"STIM1 knockdown; Orai1 pharmacological blockade; live-cell imaging; invadopodium assays; MT1-MMP localization; Src activity assay; xenograft metastasis model\",\n      \"journal\": \"Journal of Cell Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic pathway dissection (Orai1→Ca2+ oscillations→Src→invadopodium; Orai1→MT1-MMP trafficking) with in vivo validation; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"25404747\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"Heterologous expression of patient mutations; patch-clamp electrophysiology measuring Ca2+-dependent inactivation; zebrafish model for STIM1 R304W\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — electrophysiology with defined mutation plus in vivo zebrafish model; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"24591628\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation; overexpression of CSQ1 deletion mutants; Ca2+ imaging; SOCE measurement in HEK293 cells\",\n      \"journal\": \"Scientific Reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP plus Ca2+ imaging; single lab, two methods\",\n      \"pmids\": [\"26087026\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Transmission and freeze-fracture electron microscopy of STIM1- and Orai1-transfected HEK293 cells with and without thapsigargin treatment\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct structural visualization by EM at near-molecular resolution; single lab with rigorous controls\",\n      \"pmids\": [\"26351694\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Orai1-knockout mice; in vitro osteoclast and osteoblast differentiation; Ca2+ imaging; resorption pit assay; bone densitometry\",\n      \"journal\": \"Cell Calcium\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockout mouse with mechanistically specific cellular phenotypes; multiple cell-type analysis\",\n      \"pmids\": [\"23122304\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"Western blot; lectin-binding assays; Ca2+ imaging; patch-clamp; site-directed mutagenesis of N223; siRNA knockdown of ST6GAL1\",\n      \"journal\": \"Science Signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis plus knockdown plus electrophysiology; single lab, two orthogonal methods\",\n      \"pmids\": [\"26956484\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"Ca2+ imaging; patch-clamp; PKC inhibition; expression of PKC-insensitive Orai1 mutant; fluorescence microscopy in patient-derived melanoma cells\",\n      \"journal\": \"Molecular and Cellular Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — PKC-insensitive mutant rescue; electrophysiology; single lab, two orthogonal methods\",\n      \"pmids\": [\"26055321\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"siRNA knockdown; Ca2+ imaging; pharmacological inhibitors; adenoviral Orai1 siRNA in ApoE-/- mice; immunostaining\",\n      \"journal\": \"Arteriosclerosis Thrombosis and Vascular Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockdown with pathway dissection (calcineurin vs. ASK1/JNK/p38); in vivo validation; single lab\",\n      \"pmids\": [\"26916730\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"Patch-clamp electrophysiology and Ca2+ imaging of mutant ORAI1 channels expressed in HEK cells; functional characterization with/without STIM1\",\n      \"journal\": \"Human Mutation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — electrophysiology with multiple mutants and STIM1 dependence test; single lab with rigorous controls\",\n      \"pmids\": [\"28058752\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"Biochemical binding assays; CaM-binding site mapping in STIM1; functional Ca2+ imaging and patch-clamp with wild-type and constitutively active STIM1 mutants\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical dissection of CaM-STIM1 interaction plus functional consequence on Orai1 inactivation; single lab, two orthogonal methods\",\n      \"pmids\": [\"29051492\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"Concatenated SOAR heterodimers with point mutations; super-resolution microscopy; FRAP; Ca2+ oscillation measurements; co-expression experiments\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — super-resolution imaging + FRAP + functional Ca2+ measurements + defined point mutants; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"29581306\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"Super-resolution microscopy; co-immunoprecipitation; FRET; NAADP signaling; knockout cell analysis; Ca2+ imaging\",\n      \"journal\": \"Science Signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — super-resolution microscopy plus Co-IP/FRET plus knockout functional analysis; multiple orthogonal approaches\",\n      \"pmids\": [\"30563862\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"Patch-clamp electrophysiology; Ca2+ imaging; molecular dynamics simulations; expression in Stim1-/-/Stim2-/- MEFs; primary human myoblasts\",\n      \"journal\": \"Journal of Physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — electrophysiology plus molecular dynamics plus knockout MEF reconstitution; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"30382595\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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).\",\n      \"method\": \"Cysteine crosslinking; functional patch-clamp and Ca2+ imaging with STIM1 α3 mutants; proximity assay\",\n      \"journal\": \"Cell Calcium\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — crosslinking plus functional electrophysiology; single lab, two methods\",\n      \"pmids\": [\"30831274\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"Super-resolution live-cell imaging of ORAI1, STIM1, and septin 4; co-localization analysis; STIM/septin perturbation\",\n      \"journal\": \"Scientific Reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — super-resolution imaging with defined genetic perturbations; single lab\",\n      \"pmids\": [\"31346209\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation; siRNA knockdown; Ca2+ imaging; ERK phosphorylation assay; cell migration assay; in vivo lung metastasis model\",\n      \"journal\": \"Cancer Science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP (single) plus functional knockdown with pathway readout; single lab\",\n      \"pmids\": [\"31755615\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Biochemical S-acylation detection (acyl-RAC); site-directed mutagenesis of C143; Ca2+ imaging; STIM1 puncta co-localization assay\",\n      \"journal\": \"Journal of Cell Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — biochemical detection of PTM plus mutagenesis plus functional Ca2+ entry assay plus localization; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"34156466\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"Oxidomimetic mutagenesis (C195D); SOCE measurement; single-particle tracking; molecular dynamics; experimental validation of intramolecular interaction\",\n      \"journal\": \"Scientific Reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis + molecular dynamics + functional assays; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"27624281\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Astrocyte-specific Orai1 knockout mice; transcriptomics; metabolomics; Ca2+ imaging; electrophysiology; behavioral tests\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific knockout with transcriptomic, metabolic, electrophysiological, and behavioral readouts; multiple orthogonal methods\",\n      \"pmids\": [\"37679321\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation of endogenous proteins; proximity ligation assay (PLA); Fura-2 Ca2+ imaging in cortical neurons\",\n      \"journal\": \"Journal of Neurochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus quantitative PLA plus Ca2+ imaging; single lab, two orthogonal interaction methods\",\n      \"pmids\": [\"23711249\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Transcription factor binding assay (NF-κB promoter); SGK1 and AMPK gain/loss of function; Western blot; SOCE measurement\",\n      \"journal\": \"Cell Calcium\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — promoter binding plus kinase gain/loss-of-function; single lab, two methods\",\n      \"pmids\": [\"22682960\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"ORAI1 and STIM1 CRISPR knockout in HEK293-ACE2 cells; transcriptome analysis; SARS-CoV-2 infection; ORAI1 blocker/agonist modulation; IFN-β expression assay\",\n      \"journal\": \"Journal of Immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout with transcriptomics and functional infection assay; single lab, two orthogonal approaches\",\n      \"pmids\": [\"34819389\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Immunofluorescence localization; selective Orai1 inhibitor CM5480; Ca2+ imaging; in vitro secretion assays; in vivo acute pancreatitis models\",\n      \"journal\": \"Journal of Physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization plus pharmacological inhibition with in vitro and in vivo functional readouts; single lab\",\n      \"pmids\": [\"35081662\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Ca2+ imaging with spatiotemporal analysis; SEPTIN/Orai1/MLCK inhibitors and knockdown; MLC phosphorylation assay; immunostaining\",\n      \"journal\": \"Advanced Science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological and genetic pathway dissection (SEPTIN→Orai1→CaM/MLCK→actomyosin); single lab, multiple readouts\",\n      \"pmids\": [\"36960682\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"FRET; Ca2+ imaging; FRAP; TIRF microscopy; Western blot; in vivo inhalation model in wild-type and SPLUNC1-/- mice\",\n      \"journal\": \"American Journal of Respiratory Cell and Molecular Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — FRET for direct interaction plus in vivo functional validation; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"34807800\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ORAI1 (CRACM1/TMEM142A) is a plasma membrane, four-transmembrane-domain protein that forms homo- or heteromultimeric Ca2+-selective ion channels (the CRAC channel pore); conserved glutamate residues in TM1 (E106) and TM3 (E190) line the pore and determine ion selectivity; upon ER Ca2+ store depletion, the ER-resident sensor STIM1 oligomerizes, translocates to ER-PM junctions, physically binds the cytoplasmic C-terminus of Orai1 through its SOAR/CAD domain, and allosterically gates the channel open via a STIM1 α3–Orai1 TM3 gating interface; STIM1 dimers can cross-link multiple Orai1 channels to form clusters that enhance cooperativity; channel activity is negatively regulated by Ca2+-bound calmodulin disrupting the STIM1-Orai1 complex, by ROS-mediated intramolecular locking between oxidized C195 and S239, by N-glycosylation/sialic acid–Siglec interactions, and by protein kinase C-mediated phosphorylation; membrane Orai1 abundance is controlled by the SGK1/Nedd4-2 ubiquitin axis and NF-κB-driven transcription; S-acylation of C143 upon store depletion is required for Orai1 recruitment to ER-PM junctions; in immune cells (T cells, B cells, mast cells, neutrophils, platelets), Orai1-mediated Ca2+ entry activates NFAT to drive gene transcription, cytokine production, degranulation, and activation-induced cell death; in non-immune cells Orai1 regulates endothelial proliferation and tube formation, keratinocyte focal adhesion turnover via PKCβ-Calpain-FAK, cardiomyocyte hypertrophy via calcineurin/CaM KII/ERK, osteoclast fusion, and astrocyte reactivity.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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 [#0, #1]. 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 [#0, #3]. 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 [#3, #5, #22]. Activation proceeds through a defined gating interface in which the STIM1 \\u03b13 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 [#29, #32]. Recruitment of ORAI1 to STIM1 puncta requires store-depletion-triggered S-acylation at C143 [#35], and the channel is negatively regulated by Ca2+-bound calmodulin disrupting the STIM1-ORAI1 complex [#28] and by thiol oxidation at C195 locking the channel closed [#36]. Surface ORAI1 abundance is set by an SGK1/Nedd4-2 ubiquitin axis and NF-\\u03baB-driven transcription [#15, #39]. Through this Ca2+-entry activity ORAI1 drives NFAT-dependent transcription and effector functions across immune lineages\\u2014mast cell degranulation, T- and B-cell activation and activation-induced cell death, and platelet activation and thrombus formation [#6, #11, #16, #9]\\u2014and in non-immune contexts controls endothelial proliferation and tube formation, cardiomyocyte hypertrophy, keratinocyte adhesion turnover via a PKC\\u03b2-Calpain-FAK pathway, osteoclast fusion, and astrocyte reactivity [#12, #14, #18, #23, #37]. Gain-of-function ORAI1 mutations (P245L, G98S, V107M, T184M) cause tubular aggregate myopathy by either abolishing Ca2+-dependent inactivation or generating constitutively permeable channels [#20, #27, #31].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Established the molecular identity of the long-sought CRAC channel pore, answering whether ORAI1 itself conducts Ca2+ or merely supports the channel.\",\n      \"evidence\": \"Genome-wide RNAi screen plus mutagenesis of pore-lining acidic residues with patch-clamp electrophysiology\",\n      \"pmids\": [\"16921383\", \"16645049\", \"16978865\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Channel stoichiometry and the atomic architecture of the pore were not resolved\", \"Mechanism by which the channel is gated open was unknown\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Showed ORAI1 functions in partnership with STIM1, defining the two-component nature of store-operated Ca2+ entry.\",\n      \"evidence\": \"Co-overexpression of STIM1 and ORAI1 in HEK293/RBL cells with reconstitution of CRAC current by Ca2+ imaging and electrophysiology\",\n      \"pmids\": [\"16733527\", \"16766533\", \"16978865\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether STIM1-ORAI1 coupling was direct or indirect was not yet shown\", \"Required stoichiometry between the two proteins was undefined\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Defined paralog relationships, showing ORAI2/ORAI3 can heteromultimerize with ORAI1 and support CRAC current with distinct properties.\",\n      \"evidence\": \"Dominant-negative E106Q cross-inhibition and pharmacological/electrophysiological comparison in STIM1-expressing HEK293 cells\",\n      \"pmids\": [\"17442569\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Native heteromer composition in physiological cells not established\", \"Functional consequences of paralog mixing in vivo unknown\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Demonstrated the in vivo physiological requirement for ORAI1, beginning with mast cell effector function and allergy.\",\n      \"evidence\": \"Orai1-knockout mouse with degranulation, cytokine, and in vivo allergy assays\",\n      \"pmids\": [\"18059270\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream transcriptional program not dissected here\", \"Cell-type-specific contributions not separable in global knockout\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Extended ORAI1's essential role to lymphocytes and platelets, linking SOCE to adaptive immunity and hemostasis.\",\n      \"evidence\": \"Orai1-knockout mice with patch-clamp, Ca2+ imaging, proliferation, and in vivo thrombosis models\",\n      \"pmids\": [\"18591248\", \"18832659\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Transcription factors coupling Ca2+ entry to phenotype not yet mapped\", \"Tissue-specific versus developmental contributions not separated\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Provided the first dynamic, spatial picture of STIM1-ORAI1 activation, showing conformational rearrangement and co-clustering at immune synapses and ER-PM junctions.\",\n      \"evidence\": \"Live-cell FRET between tagged STIM1/ORAI1 and confocal imaging at the T cell-dendritic cell synapse with dominant-negative dissection\",\n      \"pmids\": [\"18832420\", \"18250319\", \"18987344\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of the gating conformational change not resolved\", \"Recruitment versus gating steps separable functionally but not yet structurally\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Expanded ORAI1 function to proliferative and invasive contexts in non-excitable cells, linking SOCE to endothelial cell cycle and tumor metastasis.\",\n      \"evidence\": \"RNAi/rescue with cell cycle analysis in endothelial cells and in vivo breast cancer metastasis models with pharmacological SOCE inhibition\",\n      \"pmids\": [\"18845811\", \"19185847\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream effectors linking Ca2+ entry to migration not fully defined at this stage\", \"Specificity of SOCE pharmacology in vivo limited\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Connected ORAI1 to Mendelian disease, identifying gain-of-function mutations causing tubular aggregate myopathy through altered channel inactivation or constitutive permeability.\",\n      \"evidence\": \"Heterologous expression of patient mutations (P245L) with patch-clamp measurement of Ca2+-dependent inactivation\",\n      \"pmids\": [\"24591628\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue-level pathology in muscle not mechanistically connected to channel defect\", \"Genotype-phenotype range incomplete\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Resolved how STIM1 amplifies channel activity, showing the dimeric SOAR domain cross-links ORAI1 channels to drive clustering and cooperativity.\",\n      \"evidence\": \"Concatenated SOAR heterodimers with point mutations, super-resolution microscopy, FRAP, and Ca2+ oscillation measurements\",\n      \"pmids\": [\"29581306\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative relationship between cluster size and current not fully defined\", \"Physiological tuning of cross-linking in native cells unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined the STIM1-ORAI1 gating interface, distinguishing binding from the coupling step that opens the channel.\",\n      \"evidence\": \"Cysteine crosslinking and patch-clamp with STIM1 \\u03b13 mutants mapping proximity to ORAI1 TM3\",\n      \"pmids\": [\"30831274\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Crosslinking and electrophysiology from a single lab without structural confirmation\", \"Allosteric pathway from interface to pore not resolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Resolved that channel-regulatory inputs include calmodulin-mediated inactivation and redox locking, defining negative-feedback control of ORAI1.\",\n      \"evidence\": \"Biochemical CaM-STIM1 binding mapping and oxidomimetic C195D mutagenesis with single-particle tracking and functional assays\",\n      \"pmids\": [\"29051492\", \"27624281\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Redox findings rest on a single lab with oxidomimetic surrogates\", \"Integration of multiple negative regulators in vivo not established\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified a post-translational switch required for channel recruitment, showing store-depletion-triggered S-acylation at C143 enables ORAI1 trafficking into STIM1 puncta.\",\n      \"evidence\": \"Acyl-RAC biochemistry, C143 mutagenesis, Ca2+ imaging, and STIM1 puncta colocalization\",\n      \"pmids\": [\"34156466\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Enzyme(s) catalyzing the S-acylation not identified\", \"Kinetic relationship to STIM1 oligomerization not resolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Broadened the physiological reach of ORAI1 to glia and CNS function, linking astrocyte SOCE to inflammatory gene expression and behavior.\",\n      \"evidence\": \"Astrocyte-specific Orai1 knockout mice with transcriptomics, metabolomics, electrophysiology, and behavioral testing\",\n      \"pmids\": [\"37679321\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct Ca2+-to-transcription effectors in astrocytes not fully mapped\", \"Neuronal versus glial circuit contributions not separated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the many regulatory layers (S-acylation, calmodulin, redox, glycosylation, PKC phosphorylation, SGK1/Nedd4-2, NF-\\u03baB) are integrated to set context-specific ORAI1 activity, and the atomic structure of the gated STIM1-ORAI1 complex, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified quantitative model of competing regulators\", \"No high-resolution structure of the activated STIM1-ORAI1 gating complex in the timeline\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005262\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 22, 41]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 7, 16]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [6, 11, 16]},\n      {\"term_id\": \"R-HSA-109582\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [20, 27, 31]}\n    ],\n    \"complexes\": [\"CRAC channel\"],\n    \"partners\": [\"STIM1\", \"STIM2\", \"ORAI2\", \"ORAI3\", \"RYR1\", \"TRPC1\", \"PTGER4\", \"CALM1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}