Affinage

ORAI3

Protein orai-3 · UniProt Q9BRQ5

Length
295 aa
Mass
31.5 kDa
Annotated
2026-04-29
58 papers in source corpus 45 papers cited in narrative 44 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ORAI3 is a plasma membrane calcium channel subunit that functions in both store-operated (SOCE/CRAC) and store-independent (ARC/LRC) calcium entry pathways, with roles in cell proliferation, migration, cardiac homeostasis, and vascular remodeling. In store-independent mode, ORAI3 assembles with ORAI1 as a heteropentamer (3 ORAI1 + 2 ORAI3) to form arachidonic acid/LTC4-activated ARC channels gated by plasma membrane-resident STIM1, with the ORAI3 N-terminal domain conferring selectivity for arachidonic acid activation (PMID:17991693, PMID:19622606, PMID:20818184). In store-operated mode, ORAI3 forms STIM1/STIM2-gated CRAC channels—notably replacing ORAI1 as the dominant SOCE mediator in ERα-positive breast cancer cells, certain cardiomyocytes, and multiple other cancer types—where it drives downstream ERK, Akt, NFAT, and calcineurin signaling to regulate cell cycle progression, chemoresistance, and metastasis (PMID:20395295, PMID:25213556, PMID:22993197, PMID:34065942). Cardiac-specific deletion of ORAI3 causes dilated cardiomyopathy with disrupted sarcomeric ultrastructure and mitochondrial remodeling, and ORAI3 protein stability is controlled by MARCH8-mediated ubiquitination and lysosomal degradation downstream of NFATc1 (PMID:33849280, PMID:41023307).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 2007 High

    The discovery that ORAI3 is an essential subunit of store-independent ARC channels—distinct from CRAC—established that ORAI family members form functionally distinct channel types through heteromeric assembly with ORAI1.

    Evidence Patch-clamp electrophysiology, siRNA knockdown, and dominant-negative expression in HEK293 cells stably expressing STIM1

    PMID:17991693

    Open questions at the time
    • Subunit stoichiometry of the ARC channel was unknown
    • Mechanism by which arachidonic acid activates the heteromeric channel was undefined
    • Whether ORAI3 contributes to SOCE/CRAC in any native cell type was unresolved
  2. 2008 High

    Identification of the TM2-TM3 region as the structural determinant for 2-APB-mediated STIM1-independent activation of ORAI3, and demonstration that 2-APB dilates the pore from ~3.8 Å to >5.34 Å, revealed a unique gating mechanism distinct from store-operated activation.

    Evidence Orai1–Orai3 chimera analysis, site-directed mutagenesis (E165Q), ion substitution, and patch-clamp electrophysiology

    PMID:18420579 PMID:18499656

    Open questions at the time
    • Identity of TM1 residues lining the 2-APB-activated pore was unknown
    • Whether 2-APB gating is physiologically relevant was unclear
    • Structural basis at atomic resolution was unavailable
  3. 2009 High

    Reconstitution of the ARC channel as a defined 3 ORAI1 + 2 ORAI3 heteropentamer resolved the subunit stoichiometry and confirmed that all key biophysical features—arachidonic acid activation, store independence, and PM-STIM1 requirement—are intrinsic to this assembly.

    Evidence Concatenated pentameric constructs with patch-clamp electrophysiology in HEK293 cells

    PMID:19622606

    Open questions at the time
    • Which domain of ORAI3 confers arachidonic acid selectivity was unknown
    • How PM-resident STIM1 gates the ARC channel was undefined
  4. 2010 High

    Domain-swap experiments pinpointed the ORAI3 N-terminal domain as the molecular determinant that switches channel activation from store-operated to arachidonic acid-activated, explaining why two ORAI3 subunits are required for full ARC selectivity.

    Evidence Domain substitution in concatenated heteropentamers, Ca²⁺ imaging, and patch-clamp electrophysiology

    PMID:20818184

    Open questions at the time
    • Specific N-terminal residues mediating arachidonic acid binding were not identified
    • Whether lipid binds ORAI3 directly or acts through an intermediary was unresolved
  5. 2010 High

    Demonstration that ERα-positive breast cancer cells use ORAI3 (not ORAI1) as their primary SOCE/CRAC channel established ORAI3 as a cell-type-specific SOCE mediator with oncological significance.

    Evidence siRNA knockdown, Ca²⁺ imaging, patch-clamp, and pharmacology across 10 breast cell lines

    PMID:20395295

    Open questions at the time
    • Why ER+ cells preferentially use ORAI3 over ORAI1 for SOCE was mechanistically unclear
    • Transcriptional regulation of ORAI3 in these cells was uncharacterized
  6. 2011 High

    Systematic N-terminal truncations dissected the multifaceted gating role of the ORAI3 N-terminus: the second half is required for STIM1-dependent activation, progressive truncations reduce fast inactivation and calmodulin binding, and 2-APB activation has distinct structural requirements—separating two independent gating modes.

    Evidence N-terminal deletion mutagenesis, patch-clamp electrophysiology, calmodulin binding assay

    PMID:21724845

    Open questions at the time
    • Whether calmodulin binding directly mediates fast inactivation or plays an accessory role was unresolved
    • How the N-terminus interacts with STIM1 structurally was unknown
  7. 2012 High

    ERα was identified as a transcriptional regulator of ORAI3 in ER+ breast cancer, and ORAI3-mediated SOCE was shown to activate ERK1/2, FAK, and NFAT signaling driving anchorage-independent growth and invasion, establishing a feed-forward ERα→ORAI3→proliferation axis.

    Evidence ERα siRNA reduces ORAI3 mRNA/protein, ectopic ORAI3 rescues SOCE, NFAT reporter assay, in vivo xenograft

    PMID:22993197

    Open questions at the time
    • Whether ERα directly binds the ORAI3 promoter or acts indirectly was not shown
    • Contribution of other transcription factors was uncharacterized
  8. 2013 High

    A disulfide bridge between TM2-C101 and engineered TM3-G158C provided the first functional proof of TM2–TM3 proximity in ORAI3 and showed that this crosslink alters 2-APB gating kinetics in a state-dependent manner, informing the conformational rearrangement model.

    Evidence Cysteine crosslinking mutagenesis, reducing agent (BMS) reversal, patch-clamp electrophysiology

    PMID:24081982

    Open questions at the time
    • Whether TM2–TM3 rearrangement also occurs during STIM1-mediated gating was unknown
    • No high-resolution structure was available
  9. 2014 High

    Systematic cysteine scanning of TM1 identified Q83, V77, and L70 as pore-lining residues in 2-APB-activated ORAI3, and showed that TM3-E165 approaches the pore axis only during 2-APB activation (state-dependent Cd²⁺ block of E165C), revealing a gating-induced conformational change in TM3.

    Evidence Cysteine scanning mutagenesis, Cd²⁺ block, thiol-reactive reagent (MTSEA) accessibility, patch-clamp

    PMID:24733836

    Open questions at the time
    • Whether these pore dynamics apply to STIM1-gated ORAI3 was untested
    • Three-dimensional pore architecture remained unresolved
  10. 2014 High

    LTC4 synthase was established as a required upstream activator of store-independent ORAI1/ORAI3 LRC channels in vascular smooth muscle cells, linking lipid mediator biosynthesis to ORAI3-dependent VSMC migration and neointima formation in vivo.

    Evidence LTC4S/ORAI3 knockdown, patch-clamp, balloon angioplasty rat model, lentiviral shRNA

    PMID:25540197

    Open questions at the time
    • Whether LTC4 directly binds the ORAI3 subunit was unknown
    • Contribution of other Orai heteromeric configurations in VSMCs was uncharacterized
  11. 2014 High

    STIM1/ORAI3 was identified as the critical SOCE complex in adult cardiomyocytes (enhanced in hypertrophy), and ORAI3 also mediates an arachidonic acid-activated current, establishing a dual store-dependent and store-independent role for ORAI3 in the heart.

    Evidence Co-immunoprecipitation, in vivo siRNA in cardiomyocytes, patch-clamp, Ca²⁺ imaging

    PMID:25213556

    Open questions at the time
    • Whether ORAI3 loss would cause cardiomyopathy was untested
    • Downstream signaling pathways in cardiomyocytes were poorly defined
  12. 2021 High

    Cardiac-specific ORAI3 knockout caused dilated cardiomyopathy and heart failure with disrupted sarcomere ultrastructure, mitochondrial condensation, DRP1 upregulation, and calcineurin pathway activation, demonstrating that ORAI3 is essential for cardiac homeostasis independently of ORAI1.

    Evidence Conditional and inducible cardiomyocyte-specific Orai3 knockout mice, echocardiography, electron microscopy, Ca²⁺ cycling

    PMID:33849280

    Open questions at the time
    • Whether the phenotype is driven by loss of store-operated or store-independent calcium entry was unresolved
    • Whether ORAI3 directly regulates mitochondrial dynamics or acts indirectly was unknown
  13. 2021 High

    Extracellular cysteines C226 and C232—unique to ORAI3—were identified as sensors for H₂S-mediated inhibition of SOCE; H₂S modification does not prevent STIM1 binding but blocks channel opening downstream, revealing a post-coupling regulatory mechanism.

    Evidence C226S/C232S mutagenesis, FRET, FRAP, colocalization microscopy, Ca²⁺ imaging with H₂S donors

    PMID:34788146

    Open questions at the time
    • Chemical nature of H₂S modification (persulfidation vs. polysulfide) was not determined
    • Physiological contexts where H₂S regulation of ORAI3 is relevant were uncharacterized
  14. 2021 High

    ORAI3 ICRAC was shown to be insensitive to intracellular pH changes (unlike ORAI1/ORAI2), with chimera mapping attributing pH sensitivity to the ORAI1 N-terminus and intracellular loop 2, explaining why heteromeric channels have intermediate pH responses.

    Evidence Patch-clamp with pH manipulation, Orai1–Orai3 chimera constructs

    PMID:34877682

    Open questions at the time
    • Whether pH insensitivity of ORAI3 is physiologically advantageous in acidic microenvironments (e.g., tumors) was untested
  15. 2022 High

    Genetic deletion of ORAI3 in immune cells showed it is dispensable for SOCE in B and T cells but cooperates with ORAI1 as a partially redundant SOCE subunit; combined ORAI1/ORAI3 deletion impairs B cell SOCE, NFAT activation, proliferation, and metabolic reprogramming.

    Evidence Orai3⁻/⁻ and Orai1/Orai3 double-KO mice, SOCE measurement, NFAT reporter, metabolic assays, in vivo infection model

    PMID:35861698 PMID:36803766

    Open questions at the time
    • Whether ORAI3 has a non-redundant immune function under specific challenge conditions was unresolved
    • ORAI3 contribution to myeloid cell function beyond macrophages was unexplored
  16. 2023 Medium

    An ORAI3–STIM2 complex was identified in prostate cancer cells under basal conditions; ORAI3 acts as a negative regulator of SOCE, and the ORAI3–STIM2 complex facilitates successful mitotic progression, with ORAI3 silencing causing G2/M arrest and mitotic catastrophe.

    Evidence Co-immunoprecipitation, cell cycle synchronization, Ca²⁺ imaging, western blotting

    PMID:37597301

    Open questions at the time
    • Whether STIM2 gates ORAI3 directly or serves a scaffolding role was unclear
    • The mechanism by which ORAI3 negatively regulates SOCE was undefined
    • Reciprocal IP validation was not shown
  17. 2025 High

    NFATc1 was shown to drive ORAI3 transcription in non-metastatic pancreatic cancer but simultaneously induce MARCH8-mediated ubiquitination and lysosomal degradation of ORAI3 in metastatic cells (where the MARCH8 promoter is hypomethylated), defining an epigenetically controlled post-translational switch governing ORAI3 protein levels and metastatic potential.

    Evidence ChIP, promoter methylation analysis, Co-IP (MARCH8–ORAI3), ubiquitination assay, super-resolution microscopy, in vivo metastasis model

    PMID:41023307

    Open questions at the time
    • Specific ubiquitination site(s) on the ORAI3 N-terminus were not mapped
    • Whether MARCH8 regulates ORAI3 in non-cancer contexts was unknown
  18. 2025 Medium

    An Orai1→NFAT2→ERα→Orai3 regulatory axis was defined in luminal breast cancer cells: ORAI1 controls ORAI3 protein synthesis and endo-lysosomal stability through ERα, and NFAT2 nuclear translocation attenuates ERα/ORAI3 levels, establishing cross-regulation between ORAI family members.

    Evidence Orai1 knockout MCF-7 cells, Orai1α rescue, NFAT2 nuclear translocation assay, Ca²⁺ imaging

    PMID:41172596

    Open questions at the time
    • Whether this axis operates in non-breast cancer ER+ tissues was untested
    • Direct ERα binding to the ORAI3 promoter was not demonstrated by ChIP

Open questions

Synthesis pass · forward-looking unresolved questions
  • Critical unresolved questions include: the high-resolution structure of ORAI3 (homomeric and heteromeric with ORAI1), whether arachidonic acid/LTC4 binds ORAI3 directly, the structural basis of STIM1 versus STIM2 gating specificity, and the in vivo physiological roles of ORAI3 outside the heart and immune system.
  • No cryo-EM or crystal structure of ORAI3 exists
  • Direct lipid–ORAI3 binding has not been demonstrated biochemically
  • In vivo roles in neuronal, epithelial, and vascular tissues remain underexplored

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 5 GO:0008289 lipid binding 1
Localization
GO:0005886 plasma membrane 5 GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-1643685 Disease 5 R-HSA-162582 Signal Transduction 4 R-HSA-382551 Transport of small molecules 3 R-HSA-168256 Immune System 1 R-HSA-397014 Muscle contraction 1
Partners
FAKMARCH8ORAI1STIM1STIM2TRPC6
Complex memberships
ARC channel (3×ORAI1 + 2×ORAI3 heteropentamer)STIM1–ORAI3 CRAC channel complexSTIM2–ORAI3 complex

Evidence

Reading pass · 44 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 Both Orai1 and Orai3 are essential components of the arachidonate-regulated Ca2+-selective (ARC) channels; Orai3 alone has no effect on ARC currents but specifically increases ARC channel currents when co-expressed with Orai1, and dominant-negative Orai3 or siRNA knockdown of either Orai1 or Orai3 markedly inhibits ARC channel currents without affecting CRAC channels. Patch-clamp electrophysiology, siRNA knockdown, dominant-negative expression, overexpression in cells stably expressing STIM1 The Journal of physiology High 17991693
2008 2-APB (75 µM) activates Orai3 currents independently of STIM1 and store depletion, dramatically alters ion selectivity of Orai3 by increasing the minimum pore size from ~3.8 Å to >5.34 Å, allowing monovalent cation permeation; the structural determinant for 2-APB-induced current lies in the sequence from the second to third transmembrane segment of Orai3; pore mutant E165Q partially mimics 2-APB-stimulated Orai3 permeation properties. Patch-clamp electrophysiology, site-directed mutagenesis, ion substitution experiments, chimera analysis The Journal of biological chemistry High 18420579 18499656
2008 The structural determinant responsible for 2-APB-induced current in Orai3 resides in the sequence from the second to third transmembrane segment; Orai3 can be activated by the C-terminal portion of STIM1 without store depletion; a pore mutant of Orai3 inhibited store-operated Ca2+ entry. Co-expression with STIM1 constructs, Orai1-Orai3 chimera analysis, patch-clamp electrophysiology, mutagenesis The Journal of biological chemistry High 18420579
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 activation by low concentrations of arachidonic acid, independence from store depletion, and requirement for plasma membrane-resident STIM1. Concatenated channel constructs, co-expression with dominant-negative Orai1 monomer, patch-clamp electrophysiology The Journal of physiology High 19622606
2009 Heteromeric Orai1/Orai3 channels exhibit diminished Ca2+ selectivity and robust Cs+ permeation with reduced fast inactivation compared to homomeric channels; the first extracellular loop of Orai3 differs from Orai1 by two aspartates replacing glutamates that affect selectivity; an Orai3 mutant mimicking the first loop of Orai1 recovers Ca2+ selectivity in heteromeric channels. Patch-clamp electrophysiology, site-directed mutagenesis of extracellular loop, 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 specifically determines selectivity for activation of the ARC channel by arachidonic acid; substitution of only the Orai3 N-terminal domain into an Orai1 subunit within a concatenated 3:1:1:1:1 pentamer switches the channel from store-operated to exclusively arachidonic acid-activated; two Orai3 subunits are required for full selectivity for arachidonic acid. Concatenated heteropentameric constructs, domain substitution, Ca2+ imaging, patch-clamp electrophysiology Channels (Austin, Tex.) High 20818184
2010 Native SOCE and ICRAC in estrogen receptor-positive (ER+) breast cancer cells are mediated by STIM1/STIM2 and Orai3, not by the canonical STIM1/Orai1 pathway used by ER- breast cancer cells; this was established by molecular knockdown combined with Ca2+ imaging, pharmacology, and patch-clamp electrophysiology. siRNA knockdown, Ca2+ imaging, patch-clamp electrophysiology, pharmacology across 10 breast cell lines The Journal of biological chemistry High 20395295
2011 The conserved N-terminal region of Orai3 plays a multifaceted role in current gating: progressive N-terminal truncations progressively decrease fast inactivation of Orai3 and diminish calmodulin binding; STIM1-dependent activation requires the second half of the conserved N-terminal domain; further truncations abolish STIM1-dependent activation while partially retaining 2-APB stimulation; these two activation modes have distinct structural requirements in the N-terminus. N-terminal deletion mutagenesis, patch-clamp electrophysiology, calmodulin binding assay The Journal of biological chemistry High 21724845
2011 Orai3 knockdown in ER+ MCF-7 breast cancer cells inhibits cell proliferation and arrests the cell cycle at G1 phase, associated with reduced CDK4/CDK2 and cyclins E and D1 expression and accumulation of p21Waf1/Cip1 and p53; Orai3 also mediates Ca2+ entry and contributes to intracellular calcium concentration specifically in cancer cells but not in normal MCF-10A cells. siRNA knockdown, flow cytometry, Ca2+ imaging, western blotting Journal of cellular physiology Medium 20683915
2012 ERα transcriptionally regulates Orai3 expression in ER+ breast cancer cells; ERα knockdown decreases Orai3 mRNA (~63%) and protein (~44%) without affecting Orai1; ERα knockdown decreases Orai3-mediated SOCE and ICRAC, abrogation of SOCE can be rescued by ectopic Orai3 expression; Orai3 knockdown inhibits ERK1/2 phosphorylation, FAK phosphorylation, NFAT transcriptional activity, anchorage-independent growth, and Matrigel invasion of ER+ but not ER- cells. siRNA knockdown, ectopic expression rescue, Ca2+ imaging, patch-clamp, western blotting, NFAT reporter assay, in vivo xenograft FASEB journal High 22993197
2012 Orai3 silencing in ER+ MCF-7 breast cancer cells reduces c-myc expression and activity likely through the MAP kinase pathway (decreased pERK1/2), linking Orai3-mediated SOCE to c-myc-driven cell cycle progression. siRNA knockdown, western blotting (pERK1/2, c-myc), flow cytometry Biochimica et biophysica acta Medium 23266555
2013 Orai3 constitutes a native SOCE pathway in non-small cell lung cancer cells; Orai3 silencing reduces SOCE, inhibits cell proliferation, arrests cells in G0/G1, decreases cyclin D1/E, CDK4/CDK2, and decreases Akt phosphorylation levels. siRNA knockdown, Ca2+ imaging, flow cytometry, western blotting PloS one Medium 24058448
2013 A disulfide bridge between introduced Orai3 TM3 cysteine G158C and endogenous TM2 cysteine C101 alters kinetics of 2-APB gating, as demonstrated by the slow phenotype reversal with reducing agent BMS in a state-dependent manner only during 2-APB activation; this provides functional confirmation of the proximity of TM2 and TM3 residues in the Orai3 channel. Site-directed mutagenesis, patch-clamp electrophysiology, reducing agent application (BMS), double mutant C101G/G158C The Journal of general physiology High 24081982
2013 Orai1 and Orai3 proteins promote cell proliferation independently of calcium influx per se; dominant-negative non-permeant pore mutants (E106Q-Orai1 and E81Q-Orai3) still increase cell proliferation rate; Orai3 specifically influences G2/M phase progression. siRNA knockdown, overexpression of dominant-negative pore mutants, flow cytometry, cell proliferation assays Biochimica et biophysica acta Medium 24321771
2014 TM1 residues Q83, V77, and L70 of Orai3 line the 2-APB-activated pore (Cd2+ block of cysteine mutants); TM1 residues E81C, G73A/C, and R66C abolish 2-APB sensitivity; V77C is blocked by MTSEA only in the open state (state-dependent); TM3 E165A diminishes 2-APB-activated currents while E165C shows state-dependent Cd2+ block only during 2-APB activation, indicating TM3 E165 approaches the central pore axis in the 2-APB-activated conformation. Cysteine scanning mutagenesis, thiol-reactive reagent application, patch-clamp electrophysiology, Cd2+ block experiments The Journal of general physiology High 24733836
2014 LTC4 synthase (LTC4S) is required for activation of store-independent LRC channels encoded by Orai1/Orai3 heteromultimers in vascular smooth muscle cells; LTC4S knockdown inhibits LRC currents; LTC4S and Orai3 knockdown both inhibit VSMC migration and neointima formation in vivo and are associated with more robust Akt1/Akt2 phosphorylation upon serum stimulation. siRNA/shRNA knockdown, patch-clamp electrophysiology, balloon angioplasty rat model, lentiviral shRNA delivery, migration assay The Journal of biological chemistry High 25540197
2014 Orai3 co-immunoprecipitates with STIM1 in adult cardiomyocytes; STIM1/Orai3 complex is enhanced in hypertrophied cardiomyocytes; Orai3 (not Orai1) is the critical partner of STIM1 mediating voltage-independent Ca2+ entries in hypertrophied adult cardiomyocytes; Orai3 also drives an arachidonic acid-activated inward current in cardiomyocytes. Co-immunoprecipitation, in vivo siRNA delivery to cardiomyocytes, Ca2+ imaging with Fura-2 AM, patch-clamp Cardiovascular research High 25213556
2015 VEGF triggers rapid accumulation of Orai3 at the plasma membrane surface within 2 minutes via a signaling pathway involving phospholipase Cγ1, Ca2+ release, cytosolic group IV phospholipase A2α, arachidonic acid production, and microsomal glutathione S-transferase 2 (which catalyzes LTC4 formation); Orai3 knockdown suppresses VEGF-activated Ca2+ entry and endothelial tube formation in vitro and in vivo. siRNA knockdown, immunofluorescence, surface biotinylation, Ca2+ imaging, Matrigel tube formation in vitro and in vivo Arteriosclerosis, thrombosis, and vascular biology High 26160956
2017 Orai3 (along with Orai1) is a key component of store-operated CRAC channels in dorsal root ganglion (DRG) neurons; double knockdown of Orai1 and Orai3 abolishes thapsigargin-induced membrane depolarization and increased neuronal excitability; STIM1 and STIM2 mediate SOCE in DRG neurons through Orai1 and Orai3. siRNA knockdown, confocal live cell imaging, Ca2+ imaging, patch-clamp electrophysiology Frontiers in cellular neuroscience Medium 29311831
2017 Orai3 colocalizes with IP3R at the endoplasmic reticulum and functions as a 2-APB-induced ER Ca2+ leak channel; knockdown of Orai3 inhibits 2-APB-induced ER Ca2+ leak but not thapsigargin-revealed SERCA-dependent ER Ca2+ leak; Orai1 dominant-negative (E106A) blocks the 2-APB effect on ER Ca2+; Orai3 reduction results in larger cytoplasmic Ca2+ response to thapsigargin when ER store is overloaded. Dominant-negative Orai1 expression, siRNA knockdown, synthetic Ca2+ indicators for cytoplasmic and ER Ca2+, co-localization microscopy Cell calcium Medium 28179072
2018 Orai3 overexpression in breast cancer cells promotes resistance to chemotherapeutic drugs in a calcium-dependent manner by downregulating p53 tumor suppressor via the pro-survival PI3K/Sgk-1/Sek-1 pathway; p53 degradation occurs via both Mdm2 and the E3 ubiquitin ligase Nedd4-2. High-throughput screening, siRNA knockdown and overexpression, western blotting, pathway inhibitors Cell death and differentiation Medium 29323264
2018 TRPC6 interacts with Orai3 in MCF-7 luminal breast cancer cells and is required for translocation of Orai3 to the plasma membrane upon Ca2+ store depletion; TRPC6 knockdown prevents Orai3 surface exposure and impairs SOCE in MCF-7 cells. Co-immunoprecipitation, shRNA knockdown, dominant-negative TRPC6 mutant, plasma membrane surface assay, Ca2+ imaging Cancers Medium 30223530
2018 ORAI3 and STIM1 are required for TGF-β-dependent Snai1 transcription; blocking SOCE with 2-APB paradoxically increases TGF-β-dependent Snai1 activation via AKT pathway and NF-κB (p65) binding at the Snai1 promoter; ORAI3-mediated signaling differentially regulates cell migration versus Snai1 transcription. siRNA knockdown, SOCE inhibition (2-APB), AKT pathway inhibition, NF-κB promoter binding analysis, migration assay Oncotarget Medium 30034631
2018 miR18a and miR18b positively regulate Orai3 expression and function, while miR34a represses Orai3; all three miRNAs exert their effects through direct action on the Orai3 3'UTR. Bioinformatics, 3'UTR luciferase reporter assay, miRNA mimic/inhibitor transfection, Ca2+ imaging Cell calcium Medium 30216788
2019 ORAI3 expression is regulated by HIF-1α in basal breast cancer cells; hypoxia induces ORAI3 levels through a pathway involving HIF-1α; ORAI3 silencing attenuates hypoxia-associated EGFR phosphorylation and expression of genes associated with cell migration and inflammatory/immune responses. HIF-1α siRNA knockdown, ORAI3 siRNA, western blotting, gene expression analysis Cancers Medium 30754719
2019 Inflammatory cardiac CD11b/c cells trigger a store-independent calcium influx in hypertrophied cardiomyocytes that is dependent on TNFR2 and Orai3; TNFα mimics this Orai3-driven calcium influx; Orai3 in vivo knockdown inhibits protective GSK3β phosphorylation, impairs adaptive cardiac hypertrophy (EACH), and accelerates heart failure. Co-culture experiments, TNFα treatment, pharmacological inhibition, siRNA in vivo intramyocardial injection, Ca2+ imaging Scientific reports Medium 30988334
2019 ORAI3 signaling is decreased in bronchial epithelial cells from smokers and contributes to ciliary beating; ORAI3 antagonism (GSK-7975A) alters Ca2+ influx and ciliary beating but not mucus/cytokine secretion or epithelial repair. Air-liquid interface cultures, Ca2+ imaging, pharmacological inhibition (GSK-7975A), gene expression analysis American journal of respiratory cell and molecular biology Medium 30943377
2020 The number and position of Orai3 subunits within heteromeric Orai1/Orai3 channels alter pharmacology; two or more Orai3 subunits result in large 2-APB-activated outward currents that can be activated independently of store depletion and/or STIM1; one Orai3 subunit does not alter 2-APB pharmacology; this identifies heteromeric channel subtypes with distinct pharmacological profiles relevant to prostate cancer. Concatenated channel constructs with defined stoichiometry, patch-clamp electrophysiology, 2-APB pharmacology International journal of molecular sciences High 32252254
2021 Cardiac-specific deletion of Orai3 leads to dilated cardiomyopathy and heart failure; Orai3-deficient cardiomyocytes show abnormal M- and Z-line morphology, increased condensed mitochondria, upregulation of DRP1, altered myocardial Ca2+ cycling, upregulation of TRPC6 and RCAN1 (calcineurin pathway activation); removal of Orai1 from adult cardiomyocytes does not change the Orai3cKO cardiac phenotype. Conditional and inducible cardiomyocyte-specific Orai3 knockout mice, echocardiography, ultrastructural analysis, Ca2+ cycling measurements, western blotting Journal of the American Heart Association High 33849280
2021 Orai3 regulates breast cancer cell (MDA-MB-231) migration through two mechanisms: (1) Ca2+-dependent modulation of calpain activity affecting cell adhesion and migration; (2) Ca2+-independent interaction with FAK to regulate actin cytoskeleton architecture and cell morphology. siRNA knockdown, calpain activity assay, Ca2+ imaging, co-immunoprecipitation (Orai3-FAK), F-actin staining, cell adhesion and migration assays Cells Medium 34943998
2021 ORAI3 silencing in pancreatic ductal adenocarcinoma cells increases SOCE (acting as negative regulator of SOCE), and silencing impairs tumor growth in vivo and induces mitotic catastrophe and apoptosis; ORAI3 knockdown in normal pancreatic cells decreases SOCE, demonstrating opposite roles in cancer vs. normal cells. siRNA knockdown, Ca2+ imaging, in vivo xenograft, flow cytometry, cell viability assays Biochimica et biophysica acta. Molecular cell research Medium 33798603
2021 Orai3 forms a functional SOCE channel in pancreatic cancer cells and regulates cell cycle progression, apoptosis, and migration; Orai3 controls G1 phase progression, matrix metalloproteinase expression, and EMT markers; Orai3 knockdown inhibits tumor growth and secondary metastasis in vivo xenograft models. siRNA knockdown, Ca2+ imaging, in vivo xenograft and metastasis models, flow cytometry, EMT marker analysis Cancers Medium 34885048
2021 Orai3 mediates cisplatin-resistance in NSCLC by enriching cancer stem cell populations; CDDP treatment increases Orai3 expression but not Orai1 or STIM1; Orai3 contributes to SOCE in CDDP-treated and CD133+ CSC subpopulations; Orai3-mediated chemoresistance operates through the PI3K/Akt pathway (Orai3 knockdown reduces Akt phosphorylation). siRNA knockdown, Ca2+ imaging, western blotting (Orai3, Akt pS473, CSC markers), PI3K inhibitor, ectopic overexpression Cancers Medium 34065942
2021 Orai3-mediated ICRAC is insensitive to intracellular pH changes, in contrast to Orai1 and Orai2; domain swapping between Orai1 and Orai3 identified the N-terminus and intracellular loop 2 of Orai1 as responsible for pH sensitivity; STIM1 interactions also contribute to pH dependence of Orai1 ICRAC. Patch-clamp electrophysiology, intracellular pH manipulation, Orai1-Orai3 chimera constructs, STIM1-independent Orai1 mutant The Journal of physiology High 34877682
2021 Extracellular cysteines C226 and C232 (unique to Orai3, absent in Orai1 and Orai2) mediate H2S-dependent inhibition of Orai3-mediated SOCE; mutation of either cysteine abolishes H2S inhibition; H2S modification does not affect STIM1/Orai3 puncta formation or protein-protein interaction but limits SOCE downstream of STIM1 engagement. Site-directed mutagenesis (C226S, C232S, double mutant), FRAP, colocalization microscopy, FRET, Ca2+ imaging, H2S donor treatment American journal of physiology. Cell physiology High 34788146
2022 In lung fibrosis, TGF-β1-induced SEPTIN4 promotes increased Orai3-Orai1 interaction; this Orai3/Orai1 heteromeric channel remodeling suppresses STIM1-Orai1 interaction and SOCE activity, leading to a high and stable extracellular Ca2+ influx that activates fibroblasts; Orai3 knockdown decreases TGF-β1-induced fibroblast proliferation, ECM production, NFAT1 and Calpain/ERK signaling, and glycolysis. siRNA knockdown, co-immunoprecipitation (Orai3-Orai1, STIM1-Orai1), Ca2+ imaging, overexpression, western blotting Journal of cellular and molecular medicine Medium 36128650
2022 ORAI3 is dispensable for SOCE in B cells and T cells but moderately enhances SOCE in macrophages when deleted; combined deletion of Orai1 and Orai3 (but not Orai3 alone) impairs SOCE, proliferation, survival, NFAT activation, and metabolic reprogramming in B cells; Orai3 alone is not required for humoral immunity in vivo. Orai3-/- mouse model, combined Orai1/Orai3 deletion, SOCE measurement, NFAT reporter, metabolic (mitochondrial respiration, glycolysis) assays, in vivo infection model eLife High 35861698 36803766
2023 p38 MAPK activation promotes STIM1-Orai3 association and increased cytosolic Ca2+ in response to lysophosphatidylcholine (lysoPC) and arachidonic acid (ArA); this STIM1-Orai3-dependent Ca2+ increase activates Src kinase, leading to TRPC6 externalization; Orai3 downregulation blocks lysoPC/ArA-induced Ca2+ increase, TRPC6 externalization, and preserves endothelial cell migration. siRNA knockdown, Co-immunoprecipitation (STIM1-Orai3), Ca2+ imaging, TRPC6 externalization assay, p38 inhibition, migration assay American journal of physiology. Cell physiology Medium 37093037
2023 ORAI3 and STIM2 interact under basal conditions in prostate cancer cells; ORAI3 silencing increases SOCE (Orai3 acts as negative regulator of SOCE) and causes G2/M cell cycle arrest associated with elevated CDK1-Y15/Cyclin B1, mitotic catastrophe, and Bax/Bcl-2-mediated apoptosis; STIM2 and ORAI3 expression increases in M phase while STIM1 expression decreases, defining an ORAI3-STIM2 complex that enables successful mitotic progression in prostate cancer cells. Co-immunoprecipitation (ORAI3-STIM2), siRNA knockdown, Ca2+ imaging, flow cytometry, western blotting, cell cycle synchronization Cell calcium Medium 37597301
2023 Orai3 was reconstituted into liposomes and shown to be functional; recombinant STIM1 directly opens the Orai3 channel in vitro, mediating calcium release from Orai3-containing proteoliposomes. Protein purification, reconstitution into liposomes, in vitro STIM1-Orai3 interaction and Ca2+ release assay Biochemistry. Biokhimiia Medium 37770396
2023 Orai3 promotes stemness in oral/oropharyngeal squamous cell carcinoma (OSCC) by increasing intracellular Ca2+ and upregulating the stemness transcription factor ID1; suppression of ID1 abrogates Orai3-driven cancer stem cell phenotype; the Orai3/ID1 axis is enriched in CSC populations. Ectopic overexpression, siRNA knockdown, Ca2+ imaging, ID1 expression analysis, ID1 knockdown rescue Cells Medium 37759448
2025 NFATc1 (published as NFAT2 in preprint) drives Orai3 transcription in non-metastatic pancreatic cancer cells; in invasive/metastatic pancreatic cancer cells, NFATc1 induces Orai3 lysosomal degradation by transcriptionally enhancing MARCH8 E3-ubiquitin ligase expression; MARCH8 physically interacts with Orai3 intracellular loop and ubiquitinates Orai3 at the N-terminal; the dichotomy is explained by hyper-methylation of the MARCH8 promoter in non-metastatic cells; MARCH8 restricts pancreatic cancer metastasis by targeting Orai3 degradation. ChIP, promoter methylation analysis, siRNA knockdown, overexpression, Co-immunoprecipitation (MARCH8-Orai3), ubiquitination assay, super-resolution microscopy, Ca2+ imaging The EMBO journal High 41023307
2025 Orai3 drives OSCC progression via the Ca2+/calmodulin/calcineurin/ETV4 signaling pathway; Orai3 knockdown reduces SOCE and suppresses cancer cell proliferation, migration, and invasion; calmodulin and calcineurin inhibitors further suppress these functions; Orai3 knockdown downregulates ETV4, and ETV4 overexpression rescues the suppressed phenotype; calcineurin inhibitor CsA reduces ETV4 expression. siRNA knockdown, ETV4 overexpression rescue, calmodulin/calcineurin inhibitors (W-7, CsA), Ca2+ imaging, transcriptomics FASEB journal Medium 41417281
2025 Orai1 regulates Orai3 protein synthesis and stability in luminal breast cancer cells; Orai1 knockout reduces Orai3 protein synthesis and enhances endo-lysosomal Orai3 degradation; Orai1 regulates ERα expression, and Orai1-induced NFAT2 nuclear translocation attenuates ERα and Orai3 protein content, establishing an Orai1→NFAT2→ERα→Orai3 regulatory axis. Orai1 knockout MCF-7 cells, RNAi, Orai1α rescue expression, Ca2+ imaging, western blotting, 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 135 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 97 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 51 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
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
2014 Emergence of Orai3 activity during cardiac hypertrophy. Cardiovascular research 34 25213556
2016 Orai3 is a predictive marker of metastasis and survival in resectable lung adenocarcinoma. Oncotarget 33 27835593
2020 Orai3: Oncochannel with therapeutic potential. Cell calcium 32 32659517
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 31 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 22 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 17 36803766
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 Cardiac-Specific Deletion of Orai3 Leads to Severe Dilated Cardiomyopathy and Heart Failure in Mice. Journal of the American Heart Association 16 33849280
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 10 37597301
2023 Orai3 Calcium Channel Contributes to Oral/Oropharyngeal Cancer Stemness through the Elevation of ID1 Expression. Cells 10 37759448
2022 ORAI3 is dispensable for store-operated Ca2+ entry and immune responses by lymphocytes and macrophages. The Journal of general physiology 10 35861698
2021 Orai1- and Orai2-, but not Orai3-mediated ICRAC is regulated by intracellular pH. The Journal of physiology 10 34877682
2022 Orai3 mediates Orai channel remodelling to activate fibroblast in pulmonary fibrosis. Journal of cellular and molecular medicine 9 36128650
2021 ORAI3 contributes to hypoxia-inducible factor 1/2α-sensitive colon cell migration. Physiology international 7 34161303
2023 p38 MAPK activation and STIM1-Orai3 association mediate TRPC6 externalization. American journal of physiology. Cell physiology 6 37093037
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 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 Hypoxia drives cervical cancer progression via OCT4/ORAI3-dependent glycolysis and Ca2+ signaling. Cellular and molecular life sciences : CMLS 0 41196424
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