Affinage

ORAI3

Protein orai-3 · UniProt Q9BRQ5

Length
295 aa
Mass
31.5 kDa
Annotated
2026-06-10
58 papers in source corpus 40 papers cited in narrative 39 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ORAI3 is a mammalian plasma-membrane Ca2+ channel that operates in multiple gating modes to drive Ca2+-dependent signaling in cancer, vascular, cardiac, and immune contexts (PMID:20395295, PMID:33849280). In the store-operated mode it forms a Ca2+-selective channel directly gated by STIM proteins: reconstituted Orai3 in proteoliposomes is opened by recombinant STIM1 in vitro (PMID:37770396), and Orai3 carries native SOCE/ICRAC in ER+ breast cancer cells, NSCLC, and hypertrophied cardiomyocytes (PMID:20395295, PMID:24058448, PMID:25213556). ORAI3 also assembles into store-independent arachidonate- and leukotriene-C4-regulated channels as a heteropentamer of three Orai1 and two Orai3 subunits, where the cytosolic N-terminus of Orai3 dictates selectivity for arachidonic-acid activation (PMID:17991693, PMID:19622606, PMID:20818184, PMID:25540197). Distinct N-terminal determinants govern STIM1-dependent versus 2-APB-stimulated gating; the latter dilates the pore (minimum pore size from ~3.8 to >5.34 Å) to permit nonselective cation flux, with TM1 residues (Q83, V77, L70) lining the dilated pore and TM3-E165 approaching the pore axis only in the 2-APB-activated state (PMID:18420579, PMID:18499656, PMID:21724845, PMID:24733836). Subunit stoichiometry and position within heteromeric channels tune both Ca2+ selectivity and 2-APB pharmacology (PMID:19887627, PMID:32252254), while Orai3-unique extracellular cysteines C226/C232 confer selective inhibition by H2S downstream of STIM1 engagement (PMID:34788146). ORAI3 expression is controlled by ERα, HIF-1α, Notch1/HEY1, and an Orai1-NFAT2-ERα feedback axis, and NFATc1 both transcribes ORAI3 and triggers its MARCH8-mediated lysosomal degradation in metastatic cells (PMID:22993197, PMID:30754719, PMID:41023307, PMID:41413272, PMID:41172596). Through these channels ORAI3 sustains pro-proliferative and pro-migratory signaling (ERK, Akt, FAK, c-myc, NFAT) and p53 turnover in cancer cells (PMID:22993197, PMID:23266555, PMID:29323264, PMID:34943998), and cardiac-specific Orai3 deletion causes dilated cardiomyopathy with sarcomere disruption, DRP1-driven mitochondrial fragmentation, and calcineurin activation, establishing it as essential for cardiac homeostasis (PMID:33849280).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 2007 High

    Established that Orai3, together with Orai1, is an obligatory component of store-independent arachidonate-regulated (ARC) Ca2+ channels, distinguishing it from the canonical CRAC pathway.

    Evidence Reciprocal overexpression, dominant-negative, and siRNA knockdown with patch-clamp in STIM1-expressing cells

    PMID:17991693

    Open questions at the time
    • Subunit stoichiometry of the ARC channel not yet defined
    • Molecular basis of arachidonic-acid selectivity unknown
  2. 2008 High

    Defined a STIM1-independent gating mode in which 2-APB dilates the Orai3 pore to a nonselective cation channel, revealing pharmacologically separable conformations.

    Evidence Patch-clamp with Orai1-3 chimeras, pore-size and ion-permeation measurements, E165Q and R66W mutants in HEK cells

    PMID:18420579 PMID:18499656

    Open questions at the time
    • Physiological relevance of the dilated nonselective state not established
    • Endogenous 2-APB-like activator unidentified
  3. 2009 High

    Resolved the ARC channel as a heteropentamer of three Orai1 and two Orai3 subunits with altered selectivity, defining the structural stoichiometry of store-independent gating.

    Evidence Concatenated pentameric constructs and extracellular-loop mutagenesis with patch-clamp

    PMID:19622606 PMID:19887627

    Open questions at the time
    • How STIM1 at the plasma membrane gates this fixed stoichiometry is unresolved
    • Native stoichiometry in tissues not directly measured
  4. 2010 High

    Localized arachidonic-acid activation selectivity to the cytosolic Orai3 N-terminus and demonstrated Orai3-dependent SOCE in ER+ breast cancer, linking the channel to a defined disease context.

    Evidence N-terminal domain-swap pentamers plus knockdown/electrophysiology across ten breast cell lines

    PMID:20395295 PMID:20818184

    Open questions at the time
    • Why ER+ cells use Orai3 rather than Orai1 mechanistically unclear
    • N-terminal binding partner for arachidonic-acid sensing unidentified
  5. 2011 High

    Separated the N-terminal determinants for STIM1-dependent versus 2-APB activation and tied N-terminal length to calmodulin-dependent fast inactivation.

    Evidence Stepwise N-terminal deletion mutagenesis, patch-clamp, and calmodulin binding assays

    PMID:21724845

    Open questions at the time
    • Structural basis of differential N-terminal coupling not solved
    • Role of calmodulin in native cells not tested
  6. 2012 Medium

    Placed ORAI3 in a transcriptional and signaling circuit in breast cancer, showing ERα drives its expression and that it feeds ERK/FAK/NFAT and cell-cycle progression to support tumor growth.

    Evidence ERα knockdown with Orai3 rescue, NFAT reporter, cell-cycle and xenograft assays

    PMID:20683915 PMID:22993197 PMID:23266555

    Open questions at the time
    • Direct ERα binding to the ORAI3 promoter not shown
    • Causal ordering of ERK/c-myc/NFAT events incompletely resolved
  7. 2013 High

    Mapped the 2-APB-activated pore architecture, identifying TM1 pore-lining residues and a state-dependent TM2-TM3 disulfide, defining the conformational rearrangement of the dilated channel.

    Evidence Cysteine scanning, Cd2+/MTSEA block, and redox manipulation with patch-clamp; Orai3-dependent SOCE in NSCLC

    PMID:24058448 PMID:24081982 PMID:24733836

    Open questions at the time
    • Atomic structure of the open dilated state not determined
    • Link between pore dilation and physiological gating unclear
  8. 2014 High

    Extended store-independent Orai3 signaling to vascular smooth muscle (LTC4-gated LRC channels) and to cardiomyocytes, where Orai3 is the STIM1 partner during hypertrophy.

    Evidence LTC4S knockdown, in vivo neointima model, co-IP, and in vivo siRNA with electrophysiology

    PMID:25213556 PMID:25540197

    Open questions at the time
    • Whether LRC and ARC channels are identical complexes unresolved
    • Mechanism of STIM1 partner switching during hypertrophy unknown
  9. 2015 High

    Showed VEGF rapidly traffics Orai3 to the endothelial surface via a PLCγ1-cPLA2α-arachidonic-acid-LTC4 cascade, coupling growth-factor signaling to Orai3-dependent angiogenesis.

    Evidence Surface biotinylation, immunofluorescence, knockdown, tube formation, and in vivo angiogenesis with pharmacological dissection

    PMID:26160956

    Open questions at the time
    • Trafficking machinery delivering Orai3 to the membrane unidentified
    • Whether surface Orai3 forms ARC or SOCE channels here not defined
  10. 2017 Medium

    Reported an ER-localized role for Orai3 in mediating 2-APB-induced ER Ca2+ leak distinct from SERCA, raising the possibility of a non-plasma-membrane function.

    Evidence Dominant-negative and siRNA with cytoplasmic and ER-luminal Ca2+ indicators and IP3R colocalization

    PMID:28179072

    Open questions at the time
    • Single lab; ER residence of Orai3 not independently confirmed
    • Physiological significance of the leak pathway unclear
  11. 2018 Medium

    Connected Orai3 to oncogenic protein turnover and EMT signaling, identifying p53 degradation via PI3K/Sgk-1-Mdm2/Nedd4-2 and TRPC6-dependent trafficking and TGF-β/Snai1 control.

    Evidence Overexpression/knockdown, E3-ligase identification, co-IP, ChIP/promoter-binding, and migration assays

    PMID:29323264 PMID:30034631 PMID:30223530

    Open questions at the time
    • Single-lab studies without reciprocal validation
    • Direct vs indirect role of Orai3 channel activity in p53 turnover not isolated
  12. 2019 Medium

    Identified HIF-1α as a hypoxia-driven inducer of ORAI3 in basal breast cancer and extended cardiac signaling to a TNFR2/Orai3 store-independent influx promoting hypertrophy via GSK3β.

    Evidence HIF-1α knockdown/hypoxia induction with expression readouts; conditioned-medium and in vivo siRNA with GSK3β phosphorylation

    PMID:30754719 PMID:30988334

    Open questions at the time
    • Direct HIF-1α binding at the ORAI3 locus not demonstrated
    • Channel mode mediating TNFR2-triggered influx undefined
  13. 2021 High

    Established Orai3 as essential for cardiac homeostasis through a genetic knockout causing dilated cardiomyopathy, and refined its biophysical fingerprint (pH-insensitivity, H2S inhibition, stoichiometry-dependent pharmacology).

    Evidence Cardiomyocyte-specific Orai3 knockout mice with ultrastructural and Ca2+-cycling analysis; chimeric and cysteine-mutant electrophysiology/imaging

    PMID:32252254 PMID:33798603 PMID:33849280 PMID:34788146 PMID:34877682

    Open questions at the time
    • Whether the cardiac phenotype reflects SOCE or store-independent Orai3 channels unresolved
    • In vivo relevance of H2S/pH regulation untested
  14. 2022 High

    Genetic knockout in immune cells showed Orai3 is dispensable for SOCE in T cells and only partially redundant with Orai1 in B cells, delineating cell-type-specific contributions.

    Evidence Orai3 and Orai1/3 double-knockout mice with SOCE, NFAT, metabolic, and in vivo immunization/infection readouts

    PMID:35861698 PMID:36803766

    Open questions at the time
    • Why immune-cell SOCE tolerates Orai3 loss while cancer cells depend on it unexplained
    • Macrophage enhancement of SOCE mechanism unknown
  15. 2023 Medium

    Demonstrated direct STIM1 gating of purified Orai3 in vitro and uncovered ORAI3-STIM2 basal complexes that negatively regulate SOCE to permit mitotic progression, plus stemness and endothelial migration roles.

    Evidence Proteoliposome reconstitution; co-IP, cell-cycle and apoptosis assays in prostate cancer; ID1 rescue in OSCC; p38-STIM1-Orai3-TRPC6 dissection in endothelium

    PMID:37093037 PMID:37597301 PMID:37759448 PMID:37770396

    Open questions at the time
    • Reconstitution lacks mutagenesis validation
    • STIM2-Orai3 basal complex structure and switching to active gating unresolved
  16. 2025 High

    Resolved a transcription-degradation circuit in which NFATc1 both induces ORAI3 and, via MARCH8-mediated ubiquitination and lysosomal degradation, eliminates it in metastatic cells, and defined an Orai1-NFAT2-ERα-Orai3 regulatory axis and Notch1/HEY1 control.

    Evidence ChIP/reporter, MARCH8 co-IP and ubiquitination, methylation analysis, super-resolution imaging and in vivo metastasis; Orai1-knockout rescue; Notch/HEY1 mutant assays

    PMID:41023307 PMID:41172596 PMID:41413272

    Open questions at the time
    • How methylation status of the MARCH8 promoter is set in metastatic cells not fully mechanistic
    • Integration of multiple transcriptional inputs at the ORAI3 locus unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • A unified structural explanation for how a single Orai3 protein switches between STIM1/STIM2-gated Ca2+-selective, arachidonate/LTC4-gated heteromeric, and 2-APB-gated nonselective dilated states remains undefined.
  • No high-resolution structure of any Orai3 gated state
  • Endogenous physiological trigger of pore dilation unknown
  • Mechanism selecting between channel modes in a given cell type unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 6
Localization
GO:0005886 plasma membrane 5 GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-1643685 Disease 4 R-HSA-1640170 Cell Cycle 3
Partners
FAKIP3RMARCH8ORAI1SEPTIN4STIM1STIM2TRPC6
Complex memberships
ARC channel (Orai1/Orai3 heteropentamer, 3:2)CRAC channel (STIM1/STIM2-Orai3)

Evidence

Reading pass · 39 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2008 2-APB activates Orai3 independently of STIM1 and store depletion, producing a large relatively nonselective cation current with outward rectification; chimera analysis mapped the structural determinant for 2-APB-induced current to the sequence spanning the second to third transmembrane segment of Orai3. Patch-clamp electrophysiology, Orai1-3 chimera expression in HEK cells, pharmacological application of 2-APB The Journal of biological chemistry High 18420579
2008 2-APB alters Orai3 ion selectivity by increasing its minimum pore size from ~3.8 Å to >5.34 Å, permitting monovalent cation permeation in both directions; a pore mutant (R66W) lacking store-operated activation was also resistant to 2-APB stimulation; Orai3 E165Q mutation resembled 2-APB-stimulated Orai3 in permeation properties and showed reduced 2-APB response. Patch-clamp electrophysiology, site-directed mutagenesis, ion substitution permeability assays The Journal of biological chemistry High 18499656
2007 Both Orai1 and Orai3 are essential components of the arachidonate-regulated Ca2+-selective (ARC) channels; overexpression of Orai3 alone has no effect on ARC currents, but specifically increases them when Orai1 is co-expressed; a dominant-negative Orai3 mutant specifically reduces ARC channel currents without affecting CRAC currents; siRNA knockdown of either Orai1 or Orai3 markedly inhibits ARC channel currents. Patch-clamp electrophysiology, dominant-negative expression, siRNA knockdown, overexpression in cells stably expressing STIM1 The Journal of physiology High 17991693
2009 The functional ARC channel pore is a heteropentameric assembly of three Orai1 subunits and two Orai3 subunits; expression of concatenated pentameric constructs with this 3:2 stoichiometry produces large currents with all key biophysical and pharmacological features of endogenous ARC channels including arachidonic acid activation, store-independence, and requirement for plasma membrane-resident STIM1. Concatenated Orai1/Orai3 pentameric construct expression, dominant-negative co-expression, patch-clamp electrophysiology, arachidonic acid stimulation The Journal of physiology High 19622606
2009 Heteromeric Orai1/Orai3 channels display diminished Ca2+ selectivity, robust Cs+ permeation, and reduced fast inactivation compared to homomeric forms; differences in the first extracellular loop (two aspartates in Orai3 replacing glutamates in Orai1) contribute to altered selectivity; Orai3 mutant mimicking Orai1 first loop co-expressed with Orai1 recovered Ca2+ selectivity. Patch-clamp electrophysiology, site-directed mutagenesis of extracellular loop residues, co-expression of Orai1 and Orai3 Proceedings of the National Academy of Sciences of the United States of America High 19887627
2010 The cytosolic N-terminal domain of Orai3 is specifically responsible for determining selectivity for activation of the ARC channel by arachidonic acid; substitution of the Orai3 N-terminal domain into an otherwise complete Orai1 subunit within a concatenated 3:1:1:1:1 pentamer converts the resulting channel from predominantly store-operated to exclusively arachidonic acid-activated; two Orai3 subunits are required for full selectivity. Concatenated pentameric construct expression, N-terminal domain substitution mutagenesis, Ca2+ imaging and patch-clamp electrophysiology Channels (Austin, Tex.) High 20818184
2010 Native SOCE and ICRAC in estrogen receptor-positive (ER+) breast cancer cell lines are mediated by STIM1/2 and Orai3, not Orai1; ER-negative breast cancer cells use the canonical STIM1/Orai1 pathway; established by molecular knockdown, Ca2+ imaging, pharmacology, and patch-clamp in ten breast cell lines. siRNA knockdown, Ca2+ imaging, patch-clamp electrophysiology, pharmacological inhibition across ten breast cell lines The Journal of biological chemistry High 20395295
2011 The conserved N-terminal region of Orai3 contains distinct molecular determinants for STIM1-dependent activation versus 2-APB-stimulated activation; progressive N-terminal truncations progressively decrease fast inactivation and diminish calmodulin binding; STIM1-dependent activation requires the second half of the conserved N-terminal domain, whereas 2-APB activation is partially retained with further truncations. Stepwise N-terminal deletion mutagenesis, patch-clamp electrophysiology, calmodulin binding assay The Journal of biological chemistry High 21724845
2012 ERα transcriptionally regulates Orai3 expression in ER+ breast cancer cells; ERα knockdown decreases Orai3 mRNA (~63%) and protein (~44%) without affecting Orai1; ectopic Orai3 expression rescues SOCE after ERα knockdown; Orai3 knockdown inhibits ERK1/2 and FAK phosphorylation, NFAT transcriptional activity, anchorage-independent growth, Matrigel invasion, and tumor growth in immunodeficient mice. siRNA knockdown of ERα, ectopic Orai3 re-expression, Ca2+ imaging, patch-clamp, Western blotting, NFAT reporter assay, anchorage-independent growth, Matrigel invasion, xenograft mouse model FASEB journal High 22993197
2012 Orai3 silencing in MCF-7 breast cancer cells reduces CDK4/2 and cyclin D1/E expression, accumulates p21Waf1/Cip1 and p53, arrests cell cycle at G1, and decreases Ca2+ entry and cell survival; these effects are not seen in non-cancerous MCF-10A cells upon Orai3 silencing. siRNA knockdown, Ca2+ imaging, flow cytometry, Western blotting for cell cycle proteins Journal of cellular physiology Medium 20683915
2012 Orai3 silencing in MCF-7 cells reduces c-myc expression and activity and decreases pERK1/2 levels, linking Orai3-mediated Ca2+ entry to the MAP kinase pathway and c-myc-driven cell cycle progression. siRNA knockdown, Western blotting for pERK1/2 and c-myc, flow cytometry Biochimica et biophysica acta Medium 23266555
2013 Orai3 constitutes the native SOCE pathway in non-small cell lung cancer (NSCLC) cells; Orai3 knockdown reduces SOCE, inhibits cell proliferation, arrests cells in G0/G1, downregulates cyclin D1, cyclin E, CDK4, CDK2, and decreases Akt phosphorylation. siRNA knockdown, pharmacological inhibition, Ca2+ imaging, flow cytometry, Western blotting PloS one Medium 24058448
2013 TM3 residue G158 in Orai3 forms a disulfide bridge with endogenous TM2 cysteine C101 when mutated to cysteine (G158C); this bridge slows 2-APB activation kinetics and prevents complete channel closure; reducing agent BMS reverses the slow phenotype in a state-dependent manner (only during 2-APB activation). Site-directed mutagenesis, patch-clamp electrophysiology, reducing agent application (BMS), double mutant C101G/G158C analysis The Journal of general physiology High 24081982
2014 In 2-APB-activated Orai3, TM1 residues Q83, V77, and L70 line the dilated pore (Cd2+ block potentiated at these positions); TM3 residue E165 approaches the pore axis in the 2-APB-activated state but not the store-operated state; TM1 mutants E81C, G73A/C, and R66C abolish 2-APB sensitivity; V77C is blocked by MTSEA in a state-dependent manner only when channels are open. Cysteine scanning mutagenesis, Cd2+ block, thiol-reactive reagent (MTSEA/MTSET) application, patch-clamp electrophysiology The Journal of general physiology High 24733836
2014 LTC4 (generated by LTC4 synthase from arachidonic acid) activates store-independent LRC channels encoded by Orai1/Orai3 heteromultimers in vascular smooth muscle cells; LTC4S knockdown inhibits LRC currents; Orai3 and LTC4S knockdown both inhibit Akt1/Akt2 Ser473/474 phosphorylation and VSMC migration, contributing to neointimal hyperplasia. LTC4S siRNA/shRNA knockdown, patch-clamp electrophysiology, in vivo balloon angioplasty neointima model with lentiviral shRNA, Akt phosphorylation assay, migration assay The Journal of biological chemistry High 25540197
2014 In hypertrophied adult rat ventricular cardiomyocytes, Orai3 (but not Orai1) is the critical partner of STIM1 carrying voltage-independent Ca2+ entries; Orai3 co-immunoprecipitates with STIM1, with greater STIM1 and Orai1 enriched in the Orai3 complex during hypertrophy; Orai3 also drives an arachidonic acid-activated inward current in cardiomyocytes. Co-immunoprecipitation, in vivo siRNA delivery, patch-clamp electrophysiology, Ca2+ imaging in isolated cardiomyocytes Cardiovascular research High 25213556
2015 VEGF triggers rapid (within 2 min) accumulation of Orai3 at the plasma membrane surface in human endothelial cells via a signaling pathway involving PLCγ1, Ca2+ release, cytosolic group IV phospholipase A2α, arachidonic acid, and microsomal glutathione S-transferase 2 (forming LTC4); Orai3 knockdown suppresses this VEGF-dependent Ca2+ entry and endothelial tube formation in vitro and in vivo. Immunofluorescence, cell surface biotinylation, siRNA knockdown, Ca2+ imaging, Matrigel tube formation, in vivo angiogenesis model, pharmacological pathway dissection Arteriosclerosis, thrombosis, and vascular biology High 26160956
2017 Orai3 channel colocalizes with expressed IP3R at the ER membrane and mediates 2-APB-induced Ca2+ leak from the ER; Orai3 knockdown inhibits 2-APB-induced ER Ca2+ leak without affecting thapsigargin-revealed SERCA-dependent ER Ca2+ leak; reducing Orai3 results in larger cytoplasmic Ca2+ responses after thapsigargin only when ER stores are overloaded. Dominant-negative Orai1 E106A expression, siRNA knockdown of Orai1/2/3, dual Ca2+ indicators (cytoplasmic and ER-luminal), co-localization with IP3R Cell calcium Medium 28179072
2018 Orai3 overexpression in breast cancer cells drives p53 degradation via the PI3K/Sgk-1/Sek-1 pathway, utilizing both Mdm2 and the E3 ubiquitin ligase Nedd4-2 for p53 proteolysis; this mechanism is dependent on extracellular calcium and Orai3 functionality. Orai3 overexpression, calcium removal, PI3K/Sgk-1 inhibition, Mdm2 and Nedd4-2 identification by high-throughput approach, Western blotting Cell death and differentiation Medium 29323264
2018 TRPC6 physically interacts with Orai3 in MCF7 breast cancer cells and is required for translocation of Orai3 to the plasma membrane upon Ca2+ store depletion; TRPC6 knockdown impairs Orai3-dependent SOCE in MCF7 cells. Co-immunoprecipitation, RNAi knockdown, dominant-negative TRPC6 expression, Ca2+ imaging, surface expression assay Cancers Medium 30223530
2018 ORAI3 and STIM1 are required for TGF-β-dependent Snai1 transcription; blocking SOCE paradoxically increases Snai1 activation via AKT pathway and NF-κB (p65) binding at the Snai1 promoter. siRNA knockdown of ORAI3 and STIM1, 2-APB treatment, AKT pathway analysis, ChIP/promoter-binding assays, migration assays Oncotarget Medium 30034631
2019 HIF-1α induces ORAI3 expression in basal breast cancer cell lines; ORAI3 silencing attenuates hypoxia-associated EGFR phosphorylation and expression of genes associated with cell migration and inflammatory/immune responses. HIF-1α knockdown, HIF-1α pathway induction by hypoxia, ORAI3 siRNA, Western blotting, gene expression analysis Cancers Medium 30754719
2019 Inflammatory cardiac CD11b/c cells trigger a TNFR2- and Orai3-dependent store-independent Ca2+ influx in hypertrophied cardiomyocytes; this Ca2+ influx promotes cardiomyocyte hypertrophy and resistance to oxidative stress via GSK3β phosphorylation; in vivo Orai3 knockdown during early adaptive cardiac hypertrophy impairs GSK3β phosphorylation and accelerates heart failure. Conditioned medium from cardiac CD11b/c cells, TNFα stimulation, pharmacological/siRNA Orai3 inhibition, intramyocardial siRNA injection, Ca2+ imaging, GSK3β phosphorylation assay Scientific reports Medium 30988334
2020 The number and position of Orai3 subunits within heteromeric store-operated channels alter the pharmacology of ICRAC; channels with two or more Orai3 subunits can be activated by 2-APB independently of store depletion/STIM1 and display large outward currents; a single Orai3 subunit does not alter 2-APB pharmacology compared to homomeric Orai1. Patch-clamp electrophysiology with concatenated Orai1/Orai3 constructs of defined stoichiometry and position International journal of molecular sciences Medium 32252254
2021 Orai3 regulates MDA-MB-231 breast cancer cell migration through two mechanisms: (1) a Ca2+-dependent modulation of calpain activity affecting cell adhesion; (2) a Ca2+-independent interaction with focal adhesion kinase (FAK) that regulates F-actin polymerization and cell morphology. siRNA knockdown of Orai3, calpain activity assay, cell adhesion and migration assays, F-actin staining, co-immunoprecipitation of Orai3 and FAK Cells Medium 34943998
2021 Cardiac-specific deletion of Orai3 leads to dilated cardiomyopathy characterized by abnormal sarcomere (M- and Z-line) morphology, increased DRP1-associated mitochondrial fragmentation, upregulation of TRPC6 and RCAN1 (indicating calcineurin pathway activation), and impaired myocardial Ca2+ cycling; removal of Orai1 from Orai3-deficient cardiomyocytes does not change the cardiac phenotype. Constitutive and inducible cardiomyocyte-specific Orai3 knockout mice, echocardiography, ultrastructural analysis, Western blotting, Ca2+ cycling measurements Journal of the American Heart Association High 33849280
2021 ORAI3 silencing in pancreatic ductal adenocarcinoma cells increases SOCE (in contrast to decreasing it in normal pancreatic cells), impairs proliferation, causes mitotic catastrophe and cell death, and inhibits tumor growth in vivo. siRNA knockdown, Ca2+ imaging (SOCE measurement), flow cytometry, xenograft in vivo model Biochimica et biophysica acta. Molecular cell research Medium 33798603
2021 Orai3 mediates Orai channel remodeling in pulmonary fibrosis: TGF-β1 increases SEPTIN4, which promotes Orai3-Orai1 interaction, suppressing STIM1-Orai1 interaction and SOCE activity, resulting in a high and stable extracellular Ca2+ influx that activates NFAT1 and Calpain/ERK signaling to drive fibroblast activation. Co-immunoprecipitation of Orai3-Orai1 and STIM1-Orai1, Orai3 knockdown/overexpression, BLM-induced lung fibrosis model, SEPTIN4 manipulation, Ca2+ imaging, NFAT1 and pERK Western blotting Journal of cellular and molecular medicine Medium 36128650
2021 Orai3-mediated SOCE is insensitive to changes in intracellular pH (pHi), in contrast to Orai1 (strongly pHi-dependent) and Orai2 (moderately pHi-dependent); domain swapping between Orai1 and Orai3 identified the N-terminus and intracellular loop 2 of Orai1 as responsible for pHi sensitivity. Whole-cell patch-clamp in HEK293T cells expressing Orai isoforms with STIM1, intracellular pH manipulation, Orai1/Orai3 chimeric constructs The Journal of physiology Medium 34877682
2021 Extracellular cysteines C226 and C232, unique to Orai3 (absent in Orai1 and Orai2), mediate selective inhibition of Orai3-mediated SOCE by hydrogen sulfide (H2S); mutation of either cysteine to serine abolishes H2S inhibition; H2S does not affect Orai3 membrane mobility, STIM1/Orai3 puncta formation, or STIM1-Orai3 protein-protein interactions, indicating that the inhibitory mechanism is downstream of STIM1 engagement. Site-directed mutagenesis (C226S, C232S), H2S donor (GYY4137), Ca2+ imaging, FRAP, colocalization, FRET assays in HEK293 cells American journal of physiology. Cell physiology High 34788146
2022 Deletion of ORAI3 in T cells and B cells does not impair SOCE in those cell types; combined deletion of Orai1 and Orai3, but not Orai3 alone, impairs SOCE, proliferation, survival, NFAT activation, and metabolic reprogramming in B cells; ORAI3 deletion moderately enhances SOCE in macrophages. Orai3-/- and double Orai1/3 knockout mice, SOCE measurement, flow cytometry, NFAT reporter, Seahorse metabolic assay, in vivo immunization and infection models The Journal of general physiology / eLife High 35861698 36803766
2023 ORAI3 physically interacts with STIM2 under basal conditions in prostate cancer cells; ORAI3 silencing increases SOCE and arrests cells in G2/M with elevated CDK1-Y15/Cyclin B1, leading to mitotic catastrophe via Bax/Bcl-2-mediated apoptosis and caspase-8 activation; STIM2 and ORAI3 expression increase during M phase while STIM1 decreases, suggesting an ORAI3-STIM2 complex permits mitotic progression by negatively regulating SOCE. Co-immunoprecipitation of ORAI3-STIM2, siRNA knockdown, Ca2+ imaging, flow cytometry, CDK1/Cyclin B1 Western blotting, caspase activity assay Cell calcium Medium 37597301
2023 Reconstituted Orai3 protein in proteoliposomes forms a functional channel that is directly opened by recombinant STIM1 in vitro, mediating Ca2+ release from liposomes. Protein purification, proteoliposome reconstitution, Ca2+ release assay, STIM1-Orai3 interaction in vitro Biochemistry. Biokhimiia Medium 37770396
2023 p38 MAPK activation by lysophosphatidylcholine or arachidonic acid promotes STIM1-Orai3 association in endothelial cells, increasing intracellular Ca2+ and triggering TRPC6 externalization; Orai3 downregulation blocks the lysoPC-induced Ca2+ rise and TRPC6 externalization, preserving endothelial cell migration. siRNA Orai3 knockdown, pharmacological p38 MAPK inhibition, Ca2+ imaging, TRPC6 surface expression assay, migration assays American journal of physiology. Cell physiology Medium 37093037
2023 Orai3 promotes cancer stemness in oral squamous cell carcinoma (OSCC) through upregulation of the stemness transcription factor ID1; ectopic Orai3 increases intracellular Ca2+ and acquires malignant/CSC properties; ID1 suppression abrogates the CSC phenotype induced by Orai3 overexpression. Orai3 ectopic overexpression, siRNA knockdown, Ca2+ imaging, CSC marker expression, ID1 knockdown rescue experiments Cells Medium 37759448
2024 Orai3 and STIM1 mediate store-operated Ca2+ entry in ER+ breast cancer stem-like cells (BCSCs), promoting their growth and tumorigenicity via a glycolysis-independent pathway; this is mechanistically distinct from Orai1, which interacts with SPCA2 for store-independent Ca2+ entry promoting glycolysis. siRNA knockdown, Ca2+ imaging, 3D soft fibrin gel BCSC enrichment, xenograft in vivo, glycolysis (Seahorse) assay Stem cell research & therapy Medium 39135143
2025 NFATc1 transcription factor both drives Orai3 transcription (in non-metastatic pancreatic cancer cells) and induces its lysosomal degradation (in invasive/metastatic cells) via transcriptional upregulation of MARCH8 E3-ubiquitin ligase; MARCH8 physically interacts with Orai3 intracellular loop and ubiquitinates Orai3 at the N-terminal; the dichotomy in NFATc1 function arises from differential (hyper-)methylation of the MARCH8 promoter in non-metastatic versus metastatic cells. NFATc1 ChIP and reporter assays, MARCH8 co-immunoprecipitation with Orai3, ubiquitination assay, epigenetic methylation analysis, super-resolution microscopy, siRNA/overexpression, in vivo metastasis experiments The EMBO journal High 41023307
2025 Notch1/HEY1 signaling differentially regulates Orai3 expression in breast cancer subtypes; active Notch1 and its agonist Jagged-1 alter Orai3 expression and corresponding SOCE; the non-phosphorylatable HEY1-S68A mutant mimics Notch1 effects on Orai expression, while the phosphomimetic HEY1-S68D mutant does not. Notch1 active form/Jagged-1 stimulation, DAPT (γ-secretase inhibitor), HEY1 mutant expression, Ca2+ imaging, Western blotting across breast cancer cell lines Scientific reports Medium 41413272
2025 Orai1 sustains Orai3 protein synthesis and stability in luminal breast cancer cells; Orai1 knockout decreases Orai3 protein synthesis and enhances Orai3 endo-lysosomal degradation; Orai1 also regulates ERα expression and NFAT2 nuclear translocation, which modulates ERα and Orai3 levels, establishing an Orai1-NFAT2-ERα-Orai3 regulatory axis. Orai1 knockout MCF-7 cells, RNAi silencing, ectopic Orai1 re-expression, Ca2+ imaging, Western blotting, protein synthesis/degradation assays, NFAT2 nuclear translocation assay Cell calcium Medium 41172596

Source papers

Stage 0 corpus · 58 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 A novel native store-operated calcium channel encoded by Orai3: selective requirement of Orai3 versus Orai1 in estrogen receptor-positive versus estrogen receptor-negative breast cancer cells. The Journal of biological chemistry 277 20395295
2011 Down-regulation of Orai3 arrests cell-cycle progression and induces apoptosis in breast cancer cells but not in normal breast epithelial cells. Journal of cellular physiology 159 20683915
2008 Store-dependent and -independent modes regulating Ca2+ release-activated Ca2+ channel activity of human Orai1 and Orai3. The Journal of biological chemistry 156 18420579
2012 Orai3 is an estrogen receptor α-regulated Ca²⁺ channel that promotes tumorigenesis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 154 22993197
2007 Both Orai1 and Orai3 are essential components of the arachidonate-regulated Ca2+-selective (ARC) channels. The Journal of physiology 136 17991693
2008 2-aminoethoxydiphenyl borate alters selectivity of Orai3 channels by increasing their pore size. The Journal of biological chemistry 126 18499656
2009 The molecular architecture of the arachidonate-regulated Ca2+-selective ARC channel is a pentameric assembly of Orai1 and Orai3 subunits. The Journal of physiology 98 19622606
2012 ORAI3 silencing alters cell proliferation and cell cycle progression via c-myc pathway in breast cancer cells. Biochimica et biophysica acta 94 23266555
2018 Orai3 calcium channel and resistance to chemotherapy in breast cancer cells: the p53 connection. Cell death and differentiation 88 29323264
2018 TRPC6 Channels Are Required for Proliferation, Migration and Invasion of Breast Cancer Cell Lines by Modulation of Orai1 and Orai3 Surface Exposure. Cancers 74 30223530
2011 Orai3--the 'exceptional' Orai? The Journal of physiology 74 22041188
2013 Orai3 constitutes a native store-operated calcium entry that regulates non small cell lung adenocarcinoma cell proliferation. PloS one 65 24058448
2009 Plasticity in Ca2+ selectivity of Orai1/Orai3 heteromeric channel. Proceedings of the National Academy of Sciences of the United States of America 57 19887627
2019 ORAI1 and ORAI3 in Breast Cancer Molecular Subtypes and the Identification of ORAI3 as a Hypoxia Sensitive Gene and a Regulator of Hypoxia Responses. Cancers 56 30754719
2017 Orai1 and Orai3 in Combination with Stim1 Mediate the Majority of Store-operated Calcium Entry in Astrocytes. Experimental neurobiology 53 28243166
2011 Molecular determinants within N terminus of Orai3 protein that control channel activation and gating. The Journal of biological chemistry 43 21724845
2017 Orai1 and Orai3 Mediate Store-Operated Calcium Entry Contributing to Neuronal Excitability in Dorsal Root Ganglion Neurons. Frontiers in cellular neuroscience 42 29311831
2013 Emerging roles of Orai3 in pathophysiology. Channels (Austin, Tex.) 40 23695829
2014 Emergence of Orai3 activity during cardiac hypertrophy. Cardiovascular research 36 25213556
2010 The N-terminal domain of Orai3 determines selectivity for activation of the store-independent ARC channel by arachidonic acid. Channels (Austin, Tex.) 36 20818184
2020 Orai3: Oncochannel with therapeutic potential. Cell calcium 33 32659517
2016 Orai3 is a predictive marker of metastasis and survival in resectable lung adenocarcinoma. Oncotarget 33 27835593
2014 Leukotriene-C4 synthase, a critical enzyme in the activation of store-independent Orai1/Orai3 channels, is required for neointimal hyperplasia. The Journal of biological chemistry 32 25540197
2015 Orai3 Surface Accumulation and Calcium Entry Evoked by Vascular Endothelial Growth Factor. Arteriosclerosis, thrombosis, and vascular biology 29 26160956
2013 Are Orai1 and Orai3 channels more important than calcium influx for cell proliferation? Biochimica et biophysica acta 27 24321771
2018 The calcium channel proteins ORAI3 and STIM1 mediate TGF-β induced Snai1 expression. Oncotarget 26 30034631
2019 Bronchial Epithelial Calcium Metabolism Impairment in Smokers and Chronic Obstructive Pulmonary Disease. Decreased ORAI3 Signaling. American journal of respiratory cell and molecular biology 24 30943377
2018 Regulation of proto-oncogene Orai3 by miR18a/b and miR34a. Cell calcium 23 30216788
2014 State-dependent block of Orai3 TM1 and TM3 cysteine mutants: insights into 2-APB activation. The Journal of general physiology 22 24733836
2013 Orai3 TM3 point mutation G158C alters kinetics of 2-APB-induced gating by disulfide bridge formation with TM2 C101. The Journal of general physiology 20 24081982
2021 Orai3-Mediates Cisplatin-Resistance in Non-Small Cell Lung Cancer Cells by Enriching Cancer Stem Cell Population through PI3K/AKT Pathway. Cancers 19 34065942
2021 Orai3 Calcium Channel Regulates Breast Cancer Cell Migration through Calcium-Dependent and -Independent Mechanisms. Cells 19 34943998
2017 Orai3 channel is the 2-APB-induced endoplasmic reticulum calcium leak. Cell calcium 19 28179072
2023 Orai3 and Orai1 mediate CRAC channel function and metabolic reprogramming in B cells. eLife 18 36803766
2021 Cardiac-Specific Deletion of Orai3 Leads to Severe Dilated Cardiomyopathy and Heart Failure in Mice. Journal of the American Heart Association 17 33849280
2021 ORAI3 silencing alters cell proliferation and promotes mitotic catastrophe and apoptosis in pancreatic adenocarcinoma. Biochimica et biophysica acta. Molecular cell research 16 33798603
2021 Role of Orai3 in the Pathophysiology of Cancer. International journal of molecular sciences 16 34768857
2021 Orai3 Regulates Pancreatic Cancer Metastasis by Encoding a Functional Store Operated Calcium Entry Channel. Cancers 16 34885048
2019 Cardiac inflammatory CD11b/c cells exert a protective role in hypertrophied cardiomyocyte by promoting TNFR2- and Orai3- dependent signaling. Scientific reports 14 30988334
2020 The Number and Position of Orai3 Units within Heteromeric Store-Operated Ca2+ Channels Alter the Pharmacology of ICRAC. International journal of molecular sciences 13 32252254
2024 Orai1 and Orai3 act through distinct signalling axes to promote stemness and tumorigenicity of breast cancer stem cells. Stem cell research & therapy 11 39135143
2023 Pivotal role of the ORAI3-STIM2 complex in the control of mitotic death and prostate cancer cell cycle progression. Cell calcium 11 37597301
2022 ORAI3 is dispensable for store-operated Ca2+ entry and immune responses by lymphocytes and macrophages. The Journal of general physiology 11 35861698
2022 Orai3 mediates Orai channel remodelling to activate fibroblast in pulmonary fibrosis. Journal of cellular and molecular medicine 11 36128650
2023 Orai3 Calcium Channel Contributes to Oral/Oropharyngeal Cancer Stemness through the Elevation of ID1 Expression. Cells 10 37759448
2021 Orai1- and Orai2-, but not Orai3-mediated ICRAC is regulated by intracellular pH. The Journal of physiology 10 34877682
2023 p38 MAPK activation and STIM1-Orai3 association mediate TRPC6 externalization. American journal of physiology. Cell physiology 7 37093037
2021 ORAI3 contributes to hypoxia-inducible factor 1/2α-sensitive colon cell migration. Physiology international 7 34161303
2023 Role of Orai3-Mediated Store-Operated Calcium Entry in Radiation-Induced Brain Microvascular Endothelial Cell Injury. International journal of molecular sciences 4 37047790
2021 Extracellular cysteines C226 and C232 mediate hydrogen sulfide-dependent inhibition of Orai3-mediated store-operated calcium entry. American journal of physiology. Cell physiology 4 34788146
2025 NFATc1 drives Orai3 transcription and proteolysis by harnessing epigenome differences in the MARCH8 promoter. The EMBO journal 2 41023307
2025 Orai1 plays a critical role in Orai3 synthesis and stability in luminal breast cancer cells. Cell calcium 1 41172596
2025 Hypoxia drives cervical cancer progression via OCT4/ORAI3-dependent glycolysis and Ca2+ signaling. Cellular and molecular life sciences : CMLS 1 41196424
2025 Notch1 regulates Orai1 and Orai3 expression in breast cancer cells. Scientific reports 1 41413272
2026 Structural characterization of a glycosaminoglycan sulfate from Sepia esculenta ink, and its apoptosis induction in MDA-MB-231 cells via miR-18a-5p/ORAI3 pathway mediated intracellular calcium overload. International journal of biological macromolecules 0 42002178
2025 PSG1 in Regulating Proliferation and Migration of Human Umbilical Vein Endothelial Cells Through the TGF-β/Orai3 Signaling Pathway. The journal of obstetrics and gynaecology research 0 41067714
2025 ORAI3 Modulates Oral Squamous Cell Carcinoma Metastasis Through the Ca2+/Calmodulin/Calcineurin/ETV4 Signaling Pathway. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 0 41417281
2023 Reconstitution of Calcium Channel Protein Orai3 into Liposomes for Functional Studies. Biochemistry. Biokhimiia 0 37770396

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