{"gene":"TRPC3","run_date":"2026-06-10T10:51:56","timeline":{"discoveries":[{"year":1999,"finding":"TRPC3 (and TRPC6) are directly activated by diacylglycerol in a membrane-delimited, protein kinase C-independent manner, establishing them as second-messenger-operated cation channels downstream of phospholipase C.","method":"Electrophysiology (patch clamp) in heterologous expression system; pharmacological dissection","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct in vitro electrophysiological reconstitution, PKC-independent mechanism established by pharmacology, replicated across multiple subsequent studies","pmids":["9930701"],"is_preprint":false},{"year":2003,"finding":"Receptor-mediated activation of TRPC3 in intact cells proceeds via diacylglycerol produced by phospholipase C, independently of G proteins, protein kinase C, or IP3; receptor agonists and exogenous DAG are non-additive and DAG metabolism inhibition slows reversal, confirming DAG as the proximal activator.","method":"Ca2+ imaging, electrophysiology, pharmacological inhibitors, and InsP3R-knockout DT40 cell system","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal methods in intact cells plus genetic (InsP3R-KO) confirmation, consistent with earlier reconstitution data","pmids":["12606542"],"is_preprint":false},{"year":2001,"finding":"TRPC3 channels are activated independently of IP3 receptors through DAG production from either PLC-γ or PLC-β, demonstrated in DT40 cells with all three InsP3R genes deleted.","method":"Expression of TRPC3 in DT40 InsP3R triple-knockout cells; Ca2+ imaging; pharmacological inhibition of PLC","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis using triple-KO cell line with pharmacological controls, directly tests the IP3R-coupling model","pmids":["11466302"],"is_preprint":false},{"year":1999,"finding":"TRPC3 is highly enriched in CNS neurons and co-localizes temporally and spatially with TrkB; activation of TrkB by BDNF leads to a PLC-dependent, nonselective cation conductance in pontine neurons that requires TRPC3.","method":"Immunohistochemistry, electrophysiology in brain slices, antisense knockdown","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Strong — antisense knockdown of endogenous TRPC3 in primary neurons with electrophysiological readout, replicated in multiple neuron types","pmids":["10677043"],"is_preprint":false},{"year":2003,"finding":"N-linked glycosylation at a single extracellular site (e2 loop) is a major determinant of TRPC3 constitutive activity; TRPC3 is monoglycosylated compared to dually glycosylated TRPC6, and engineering an additional glycosylation site into TRPC3 markedly reduces its basal activity.","method":"Site-directed mutagenesis of NxS/T glycosylation sites, immunoblotting, electrophysiology, Ca2+ imaging in HEK293 cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mutagenesis combined with electrophysiology and fluorescence imaging; reciprocal gain- and loss-of-function in single lab","pmids":["12970363"],"is_preprint":false},{"year":2004,"finding":"Protein kinase G (PKG) directly phosphorylates TRPC3 at Thr-11 and Ser-263, inhibiting store-operated Ca2+ influx mediated by TRPC3; point mutations T11A and S263Q abolish cGMP/PKG-dependent inhibition.","method":"In vitro PKG phosphorylation assay on purified TRPC3 protein; site-directed mutagenesis; Ca2+ imaging in HEK293 cells stably expressing PKG","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay with purified protein plus mutagenesis and functional Ca2+ readout in cells","pmids":["14983059"],"is_preprint":false},{"year":2004,"finding":"Protein kinase C negatively regulates TRPC3 by phosphorylating Ser-712; a S712A mutant is resistant to PMA-induced inhibition and shows greater receptor-stimulated Ca2+ entry than wild-type TRPC3.","method":"Site-directed mutagenesis, in vivo phosphorylation assay, electrophysiology, Ca2+ imaging in HEK293 cells","journal":"Molecular pharmacology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mutagenesis combined with phosphorylation assay and functional readouts; single lab, multiple orthogonal methods","pmids":["15533987"],"is_preprint":false},{"year":2005,"finding":"PLC-γ1 binds to TRPC3 via complementary partial pleckstrin homology (PH) domains; the partial PH domain of PLC-γ1 interacts with a PH-like domain in TRPC3 to mediate lipid binding and control cell-surface expression of TRPC3.","method":"Co-immunoprecipitation, domain mapping, gestalt PH-domain algorithm, cell-surface expression assay","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Moderate — co-IP plus domain mapping with functional surface-expression readout in single lab; published in Nature","pmids":["15744307"],"is_preprint":false},{"year":2006,"finding":"TRPC3 and TRPC4 associate to form a redox-sensitive heteromeric cation channel in endothelial cells; FRET shows close proximity between TRPC4 N-terminus and TRPC3 C-terminus; co-expression generates channels with distinct biophysical properties; dominant-negative TRPC4 suppresses TRPC3-related currents in both HEK293 and native endothelial cells.","method":"Co-immunoprecipitation, FRET, electrophysiology, dominant-negative suppression in HEK293 and porcine aortic endothelial cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — four independent lines of evidence including FRET, co-IP, electrophysiology, and dominant-negative in native cells","pmids":["16537542"],"is_preprint":false},{"year":2006,"finding":"TRPC3 interacts functionally with RyR1 to regulate gain of SR Ca2+ release during excitation-contraction coupling in skeletal muscle; knockdown of TRPC3 reduces RyR1 Ca2+ release channel activity and alters expression of triadic proteins (TRPC1, calsequestrin, triadin, junctophilin 1).","method":"Retroviral siRNA knockdown in primary skeletal myoblasts; Mn2+ influx, Ca2+ imaging with Fura-2 and Fluo-4; immunoblot","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean knockdown with multiple functional readouts; indirect functional coupling (no direct binding shown)","pmids":["16484216"],"is_preprint":false},{"year":2008,"finding":"TRPC3 interacts directly with six triadic proteins (TRPC1, JP2, homer, mitsugumin 29, calreticulin, calmodulin) in skeletal muscle in a Ca2+-independent manner, but shows no direct interaction with RyR1; TRPC1 is identified as a physical link between TRPC3 and RyR1.","method":"MALDI-TOF MS of cross-linked triadic vesicles, co-immunoprecipitation from primary mouse myotubes","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS identification plus co-IP; direct binding confirmed for six partners; absence of TRPC3-RyR1 direct interaction is a confirmed negative","pmids":["18215135"],"is_preprint":false},{"year":2008,"finding":"TRPC3 interacts with RACK1 via N-terminal residues Glu-232, Asp-233, Glu-240, and Glu-244; this interaction determines plasma membrane localization of TRPC3 and controls IP3R-RACK1 association and IP3-dependent intracellular Ca2+ release.","method":"Site-directed mutagenesis of TRPC3, co-immunoprecipitation, surface expression assay, Ca2+ imaging in HEK293 cells, siRNA knockdown","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — mutagenesis identifying specific residues, co-IP, surface expression, and functional Ca2+ readouts in same study","pmids":["18755685"],"is_preprint":false},{"year":2008,"finding":"Erythropoietin regulates Ca2+ influx through TRPC3 via a PLC-γ-mediated process requiring interaction of PLC-γ and IP3R with TRPC3; TRPC3 Tyr-226 is critical for Epo-dependent activation; C-terminal domains (residues 671–746) confer Epo-responsiveness distinguishing TRPC3 from TRPC6.","method":"Co-immunoprecipitation, site-directed mutagenesis of TRPC3 (Y226F, IP3R-binding domain mutants), Ca2+ imaging in HEK293T cells and primary erythroid precursors, siRNA knockdown of PLC-γ","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — mutagenesis + co-IP + functional Ca2+ readouts + primary cell validation in single study","pmids":["18276585"],"is_preprint":false},{"year":2009,"finding":"A gain-of-function point mutation T635A in the S4-S5 linker of TRPC3 causes altered channel gating, impairs Purkinje cell dendritic arbor development, and leads to Purkinje cell loss and cerebellar ataxia in moonwalker mice.","method":"ENU mutagenesis screen, Sanger sequencing, electrophysiology, histology, behavioral testing in mice","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — identified causative mutation with electrophysiological characterization and histological/behavioral phenotyping; replicated in subsequent studies","pmids":["19351902"],"is_preprint":false},{"year":2009,"finding":"The pyrazole compound Pyr3 selectively and directly inhibits TRPC3 channels; the trichloroacrylic amide group confers TRPC3 selectivity; direct action on TRPC3 protein confirmed by photoaffinity labeling.","method":"Electrophysiology, structure-activity relationship studies, photoaffinity labeling, Ca2+ imaging in DT40 B cells and cardiomyocytes","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — photoaffinity labeling directly demonstrates binding to TRPC3 protein; SAR studies plus functional assays; replicated widely","pmids":["19289841"],"is_preprint":false},{"year":2010,"finding":"TRPC3 functions both as a Ca2+-permeable channel and a protein scaffold for PKCβ at the plasma membrane; TRPC3 deficiency impairs DAG-activated cation currents and sustained PKCβ translocation to the plasma membrane, reducing ERK activation after BCR stimulation; TRPC3 directly associates with PKCβ.","method":"TRPC3-deficient DT40 B cells, electrophysiology, live-cell imaging of PKCβ-GFP, co-immunoprecipitation, ERK activation assay","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic deficiency model, electrophysiology, live imaging, and co-IP; multiple orthogonal methods in one study","pmids":["20179100"],"is_preprint":false},{"year":2016,"finding":"TRPC3 physically interacts with NADPH oxidase 2 (Nox2) at specific C-terminal sites, protecting Nox2 from proteasomal degradation and amplifying Ca2+-dependent Nox2 activation; Nox2 also stabilizes TRPC3 protein; disruption of the TRPC3-Nox2 complex by a C-terminal polypeptide abolishes TRPC3-regulated ROS production without affecting TRPC3-mediated Ca2+ influx.","method":"Co-immunoprecipitation, proteasome inhibitor experiments, C-terminal minipeptide competition, ROS assays, Ca2+ imaging, pressure overload mouse model","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — co-IP + peptide disruption dissecting ROS from Ca2+ functions + in vivo mouse model; replicated in multiple subsequent publications","pmids":["27833156"],"is_preprint":false},{"year":2016,"finding":"TRPC3 mediates RhoA activation and fibrotic responses through interaction with microtubule-associated GEF-H1; inhibition of TRPC3 attenuates GEF-H1 activation and Rho-mediated fibrosis in pressure-overloaded hearts; Nox2 inhibition also attenuates stretch-induced GEF-H1 activation, placing it downstream of TRPC3-Nox2.","method":"Proteomic analysis, co-immunoprecipitation, pharmacological TRPC3 inhibition, pressure overload mouse model, RhoA activity assays","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — proteomic identification plus co-IP plus in vivo model with pharmacological inhibition; consistent with established TRPC3-Nox2 axis","pmids":["27991560"],"is_preprint":false},{"year":2017,"finding":"TRPC3 mediates acute catecholamine secretion triggered by the β-arrestin-1-biased AT1R agonist TRV120027; TRV120027 promotes recruitment of TRPC3 or PLCγ to the AT1R-β-arrestin-1 signaling complex; blocking β-arrestin-1–PLCγ interaction with a TAT-P1 peptide abolishes TRPC3 activation.","method":"Co-immunoprecipitation, TAT-P1 peptide competition, Ca2+ imaging, catecholamine secretion assay, β-arrestin chimera replacement","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — co-IP + peptide disruption + functional readout; mechanistic dissection of arrestin-PLCγ-TRPC3 axis","pmids":["28181498"],"is_preprint":false},{"year":2018,"finding":"Cryo-EM structure of human TRPC3 at 4.4 Å resolution reveals a tetrameric two-layer architecture with N-terminal ankyrin repeats and C-terminal coiled-coil contributing to inter-subunit contacts; the related TRPC6 structure with inhibitor BTDM shows the inhibitor wedges between S5-S6 pore domain and voltage sensor-like domain.","method":"Single-particle cryo-electron microscopy","journal":"Cell research","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure at near-atomic resolution providing molecular architecture; includes inhibitor-bound TRPC6 as functional reference","pmids":["29700422"],"is_preprint":false},{"year":2022,"finding":"PI(4,5)P2 regulates TRPC3 through three independent modes: (1) PLC-dependent hydrolysis generates DAG that interacts with lipid-binding site 2 in the pore; (2) PI(4,5)P2 interacts with lipid site 1 to inhibit TRPC3 opening and gate DAG access to site 2; (3) PI(4,5)P2 is required for receptor-stimulated changes in pore ionic selectivity. TRPC3 requires recruitment to ER/PM junctions via an FFAT motif that interacts with ER-resident VAPB.","method":"Electrophysiology, mutagenesis of lipid-binding sites, identification and mutation of FFAT motif, co-immunoprecipitation of VAPB-TRPC3","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple mutagenesis experiments with defined lipid-binding sites, FFAT-VAPB interaction, and electrophysiological functional validation in one rigorous study","pmids":["35416932"],"is_preprint":false},{"year":2006,"finding":"PKC-mediated inhibition of TRPC3 is partly indirect, operating through PKG in vascular endothelial cells; PKG inhibitors significantly reduce PMA-induced inhibition of TRPC3 in native endothelial cells, linking the two kinase pathways.","method":"Ca2+ imaging, pharmacological inhibitors of PKC and PKG, point mutants T11A-S263Q, endothelial cell experiments","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis plus pharmacological dissection in both overexpression and native cells; single lab but two cell systems","pmids":["16331690"],"is_preprint":false},{"year":2004,"finding":"TRPC3 mediates UTP-induced (pyrimidine receptor-activated) depolarization and constriction of cerebral artery smooth muscle cells, but not myogenic (pressure-induced) responses; TRPC6 mediates myogenic depolarization, indicating differential regulation of closely related channels by receptor vs. mechanical stimuli.","method":"Antisense oligodeoxynucleotide knockdown of TRPC3 or TRPC6 in cerebral arteries; patch clamp; pressure myography","journal":"American journal of physiology. Heart and circulatory physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — antisense knockdown with electrophysiological and contractility readouts in native tissue; single lab","pmids":["15604128"],"is_preprint":false},{"year":2009,"finding":"TRPC3 and TRPC1 are co-expressed in vascular smooth muscle cells and co-immunoprecipitate; both contribute to UTP-stimulated nonselective cation currents; NO/cGMP/PKG signaling inhibits TRPC1/TRPC3 and this inhibition contributes to NO-mediated vasorelaxation.","method":"Co-immunoprecipitation, intracellular antibody blockade in patch clamp, PKG inhibitor (KT5823), vessel myograph relaxation assay in rat carotid artery","journal":"American journal of physiology. Heart and circulatory physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus functional patch clamp with intracellular antibody blockade and vessel pharmacology; single lab","pmids":["19502552"],"is_preprint":false},{"year":2012,"finding":"TRPC3 and TRPC6 are required for normal mechanosensation: loss of TRPC3 alone shifts rapidly-adapting mechanosensitive currents to intermediate-adapting currents in DRG neurons; double TRPC3/TRPC6 KO silences half of RA-current neurons, impairs light touch, and causes hearing and vestibular deficits; co-expression of TRPC3 and TRPC6 in sensory neuron cell lines induces FM1-43-sensitive mechanically gated currents.","method":"Single and double KO mice, patch clamp of DRG neurons and cochlear hair cells, behavioral testing, heterologous co-expression","journal":"Open biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic double-KO with multiple electrophysiological and behavioral readouts plus heterologous reconstitution","pmids":["22724068"],"is_preprint":false},{"year":2015,"finding":"TRPC3 co-localizes with NCX1 in cardiomyocytes and forms a micro/nanodomain; TRPC3 activation by GSK1702934A or angiotensin II promotes NCX1 currents and transiently causes spatial uncoupling of TRPC3 from NCX1, leading to Ca2+ overload and arrhythmogenesis; pro-arrhythmic effects are prevented by NCX inhibition.","method":"Immunocytochemistry colocalization, electrophysiology in TRPC3-overexpressing cardiomyocytes, Langendorff heart preparation, NCX inhibitor 3',4'-dichlorobenzamil","journal":"Cardiovascular research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — colocalization plus functional electrophysiology and pharmacology in transgenic mouse model; single lab","pmids":["25631581"],"is_preprint":false},{"year":2022,"finding":"TRPC3 acts as a negative regulator of IP3 receptor-mediated Ca2+ release at the ER/mitochondria interface; TRPC3 downregulation in senescent fibroblasts leads to elevated cytosolic/mitochondrial Ca2+ oscillations, increased mitochondrial Ca2+ load, and elevated OXPHOS; re-expression of TRPC3 in senescent cells reduces mitochondrial Ca2+ and promotes escape from oncogene-induced senescence.","method":"TRPC3 re-expression in senescent cells, mitochondrial Ca2+ imaging, OCR measurement, xenograft tumor assay","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — rescue experiment with functional Ca2+ and metabolic readouts plus in vivo tumor model; single lab","pmids":["35177596"],"is_preprint":false},{"year":2017,"finding":"TRPC3-Nox2 complex mediates doxorubicin-induced myocardial atrophy; cardiomyocyte-specific expression of TRPC3 C-terminal minipeptide inhibits TRPC3-Nox2 coupling and suppresses doxorubicin-induced cardiomyocyte size reduction and LV dysfunction without reducing hypoxic stress.","method":"Cardiomyocyte-specific transgenic minipeptide expression, Nox2 co-IP, morphometric analysis, echocardiography in mice","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic minipeptide dissection of complex in vivo, consistent with established TRPC3-Nox2 mechanism across multiple papers","pmids":["28768915"],"is_preprint":false},{"year":2011,"finding":"TRPC3 TRP domain residues (DDKPS) and the distal C-terminal AMP-activated protein kinase (AMPK) binding site are required for erythropoietin-induced TRPC3 activation and cytoskeletal association/plasma membrane insertion; chimeric TRPC6 channels gain Epo responsiveness when given TRPC3 TRP domain plus C2/AMPK site.","method":"Site-directed mutagenesis, TRPC3/TRPC6 chimeric channels, Ca2+ imaging, cell surface expression assay in HEK293T and primary erythroblasts","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — systematic mutagenesis and chimera approach; functional readouts in heterologous and primary cells; single lab","pmids":["21757714"],"is_preprint":false},{"year":2010,"finding":"Thrombin upregulates TRPC3 protein in cortical astrocytes via PAR-1/ERK/JNK/NF-κB signaling; TRPC3-mediated Ca2+ signaling feeds forward to further increase its own expression; TRPC3 knockdown inhibits thrombin-induced astrocyte morphological changes, S100B upregulation, and proliferation.","method":"siRNA knockdown, pharmacological inhibitors (Pyr3, BAPTA-AM, 2-APB), Western blot, immunofluorescence, proliferation assay in cortical astrocytes and in vivo PAR-1 agonist injection","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with multiple functional endpoints plus in vivo confirmation; single lab","pmids":["20881130"],"is_preprint":false},{"year":2019,"finding":"TRPC3 regulates triple-negative breast cancer cell proliferation and apoptosis resistance through a TRPC3-RASA4-MAPK signaling cascade: Ca2+ influx through TRPC3 sustains RASA4 localization on the plasma membrane, where it suppresses Ras-MAPK pathway activation.","method":"Subcellular fractionation, Western blot, Pyr3 pharmacology, dominant-negative TRPC3, proliferation and apoptosis assays, RASA4 membrane localization assay","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — subcellular fractionation plus pharmacological and dominant-negative manipulations with functional readouts; single lab","pmids":["31003514"],"is_preprint":false},{"year":2019,"finding":"TRPC3-Nox2 complex mediates nutritional deficiency-induced cardiomyocyte atrophy through extracellular ATP/P2Y2 receptor signaling; knockdown of either TRPC3 or Nox2 suppresses ATP-mediated Nox2 protein increases, ROS production, and cardiomyocyte atrophy.","method":"siRNA knockdown of TRPC3 and Nox2, co-IP, ROS measurement, cardiomyocyte size measurement in neonatal rat cardiomyocytes","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus knockdown of both components with functional readouts; consistent with established TRPC3-Nox2 axis","pmids":["31278358"],"is_preprint":false},{"year":2021,"finding":"TRPC3 and NALCN together form sustained inward currents responsible for the slow depolarization driving pacemaking in nigral dopamine neurons; specific blockade of TRPC3 abolishes pacemaking, but TRPC3 KO mice retain normal pacemaking due to compensatory NALCN upregulation.","method":"Pharmacological TRPC3 blockade, TRPC3 KO and NALCN blockade in mouse substantia nigra slice electrophysiology; NALCN mRNA and protein quantification","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — pharmacological and genetic dissection with electrophysiology; compensatory mechanism verified by molecular quantification","pmids":["34409942"],"is_preprint":false},{"year":2012,"finding":"STIM1L, a splice variant of STIM1, binds more abundantly to TRPC3 (and TRPC6) than canonical STIM1, and tends to suppress receptor-operated Ca2+ entry via TRPC3 and TRPC6 more strongly than STIM1; co-immunoprecipitation confirms STIM1L-TRPC3 physical association.","method":"Co-immunoprecipitation, Ca2+ imaging (thapsigargin and endothelin-1 protocols), HEK293 cells stably expressing ETA receptor","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP plus functional Ca2+ measurements; single lab","pmids":["23068106"],"is_preprint":false},{"year":2021,"finding":"Progesterone receptor isoform B (PGR-B) suppresses uterine contractility by downregulating TRPC3 (and OXTR) while upregulating PLCL2, reducing oxytocin signaling; PGR-B overexpression in smooth muscle results in prolonged gestation and labor dystocia.","method":"Transgenic mice overexpressing PGR-A or PGR-B in smooth muscle, uterine RNA sequencing, ex vivo and in vivo contractility measurement, CRISPRa-based functional assay of PLCL1/2","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transcriptomic + CRISPRa functional validation + in vivo transgenic model; TRPC3 is one of multiple downstream targets identified","pmids":["33707208"],"is_preprint":false},{"year":2016,"finding":"TRPC3 channels are required for hypothalamic glucose detection: whole-body and MBH-specific TRPC3-deficient mice show impaired anorectic response to intracerebroventricular glucose, blunted insulin secretion response to intracarotid glucose, and reduced Ca2+ responses to glucose in mediobasal hypothalamus GE neurons.","method":"Constitutive and conditional TRPC3 KO mice, in vivo food intake and insulin secretion assays, in vitro Ca2+ imaging of freshly dissociated MBH neurons, pharmacological inhibition with Pyr3","journal":"Diabetes","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO plus pharmacology plus in vitro Ca2+ imaging; multiple endpoints and two KO models","pmids":["27899482"],"is_preprint":false},{"year":2019,"finding":"TRPC3 is located at T-tubules of embryonic stem cell-derived cardiomyocytes; TRPC3 current contributes to diastolic depolarization (phase 4), local Ca2+ release, and NCX current; reducing TRPC3 current decreases action potential rate and RyR2/phospholamban phosphorylation.","method":"Immunocytochemistry, whole-cell patch clamp, confocal Ca2+ imaging, combined current and voltage clamp, dominant negative TRPC3 construct in mESC-derived cardiomyocytes","journal":"International journal of cardiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — electrophysiology plus Ca2+ imaging with dominant-negative construct; single lab, multiple readouts","pmids":["26512833"],"is_preprint":false},{"year":2022,"finding":"PLAA inhibits METTL3 expression via ubiquitin-mediated degradation; METTL3 stabilizes TRPC3 mRNA via m6A modification; reduced TRPC3 expression following PLAA upregulation decreases intracellular Ca2+ and suppresses ovarian cancer cell migration and invasion.","method":"Co-IP/ubiquitin assay, m6A-seq/RIP, CRISPR KO, Ca2+ imaging, xenograft orthotopic mouse model","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic chain from PLAA to METTL3 to m6A-TRPC3 mRNA established by co-IP and m6A assays with functional in vivo readout; single lab","pmids":["35869392"],"is_preprint":false}],"current_model":"TRPC3 is a receptor-operated, non-selective cation channel that is directly and PKC-independently activated by diacylglycerol generated downstream of PLC-coupled receptors; its activity is negatively regulated by PKC phosphorylation at Ser-712 and by PKG phosphorylation at Thr-11/Ser-263; channel localization to the plasma membrane is controlled by PLC-γ1 via complementary PH-like domains and by RACK1-mediated scaffolding; PI(4,5)P2 regulates TRPC3 through dual lipid-binding sites and requires FFAT-VAPB interaction for ER/PM junction targeting; beyond ion conduction, TRPC3 acts as a protein scaffold (for PKCβ, Nox2, NCX1, GEF-H1) and as a positive regulator of ROS production by stabilizing Nox2 against proteasomal degradation, thereby encoding Ca2+-influx signals into ROS-mediated cardiac fibrosis and atrophy; in the cerebellum, a gain-of-function T635A mutation disrupts Purkinje cell dendritic development and causes ataxia, while normal TRPC3 supports mGluR1-mediated slow EPSPs and Purkinje cell heterogeneity; in the substantia nigra, TRPC3 and NALCN together drive dopamine neuron pacemaking; in erythroid cells, TRPC3 is activated by erythropoietin through PLCγ and IP3R interactions requiring specific TRP-domain and C-terminal AMPK-binding site residues."},"narrative":{"mechanistic_narrative":"TRPC3 is a receptor-operated, non-selective cation channel that translates phospholipase C signaling into Ca2+ influx and downstream cellular responses across neurons, cardiomyocytes, smooth muscle, and erythroid cells [PMID:9930701, PMID:12606542]. It is directly and PKC-independently gated by diacylglycerol produced when PLC-coupled receptors are engaged, with receptor agonists and exogenous DAG acting non-additively and independently of G proteins, IP3, or IP3 receptors [PMID:9930701, PMID:12606542, PMID:11466302]. Channel gating and surface expression are tuned by post-translational and lipid inputs: N-linked glycosylation of an extracellular e2 loop restrains constitutive activity [PMID:12970363], PKC phosphorylation at Ser-712 and PKG phosphorylation at Thr-11/Ser-263 inhibit the channel [PMID:14983059, PMID:15533987], and PI(4,5)P2 regulates opening through dual pore lipid-binding sites that also gate DAG access, while an FFAT motif recruits TRPC3 to ER/PM junctions via ER-resident VAPB [PMID:35416932]. Cryo-EM defines a tetrameric two-layer architecture with N-terminal ankyrin repeats and a C-terminal coiled-coil forming inter-subunit contacts [PMID:29700422]. Surface localization is controlled by PLC-γ1 through complementary PH-like domains and by N-terminal RACK1 interactions [PMID:15744307, PMID:18755685]. Beyond ion conduction, TRPC3 functions as a protein scaffold, directly binding PKCβ, NADPH oxidase 2 (Nox2), NCX1, and GEF-H1, and it stabilizes Nox2 against proteasomal degradation to amplify Ca2+-dependent ROS production that drives cardiac fibrosis and atrophy [PMID:20179100, PMID:27833156, PMID:27991560, PMID:25631581, PMID:28768915]. Physiologically, TRPC3 supports BDNF/TrkB-evoked cation currents in neurons [PMID:10677043], partners with NALCN to drive nigral dopamine neuron pacemaking [PMID:34409942], mediates mechanosensation together with TRPC6 [PMID:22724068], and contributes to hypothalamic glucose sensing [PMID:27899482]; a gain-of-function T635A mutation in the S4-S5 linker disrupts Purkinje cell dendritic development and causes cerebellar ataxia in moonwalker mice [PMID:19351902].","teleology":[{"year":1999,"claim":"Established the activation logic of TRPC3 by showing it is gated directly by diacylglycerol independently of PKC, defining it as a second-messenger-operated channel downstream of PLC rather than a store-operated channel.","evidence":"Patch-clamp electrophysiology with pharmacological dissection in heterologous cells; antisense knockdown linking endogenous TRPC3 to TrkB/BDNF-evoked currents in pontine neurons","pmids":["9930701","10677043"],"confidence":"High","gaps":["Did not resolve the molecular DAG-binding site","Native receptor pathways coupling to TRPC3 not yet enumerated"]},{"year":2001,"claim":"Resolved whether IP3 receptors are required for TRPC3 gating, showing activation proceeds via DAG from either PLC-γ or PLC-β in cells lacking all IP3 receptors.","evidence":"Expression of TRPC3 in DT40 InsP3R triple-knockout cells with Ca2+ imaging and PLC inhibition; confirmed in intact cells with InsP3R-KO controls","pmids":["11466302","12606542"],"confidence":"High","gaps":["Did not exclude context-dependent IP3R modulation in other cell types","Proximal lipid-channel interaction not structurally defined"]},{"year":2003,"claim":"Identified extracellular glycosylation as a determinant of basal channel activity, explaining why TRPC3 is more constitutively active than TRPC6.","evidence":"Site-directed mutagenesis of NxS/T sites with immunoblotting and electrophysiology in HEK293 cells","pmids":["12970363"],"confidence":"High","gaps":["Mechanism by which glycosylation alters gating not defined","Single-lab result"]},{"year":2004,"claim":"Defined kinase-mediated negative regulation, showing PKG (Thr-11/Ser-263) and PKC (Ser-712) directly phosphorylate and inhibit TRPC3.","evidence":"In vitro kinase assays on purified TRPC3, phospho-site mutagenesis, and Ca2+ imaging in HEK293 cells","pmids":["14983059","15533987"],"confidence":"High","gaps":["Crosstalk between the two kinase inputs not yet ordered","Physiological triggers of each phosphorylation in native cells unclear"]},{"year":2005,"claim":"Showed channel trafficking is controlled by lipid-domain protein interactions, with PLC-γ1 binding TRPC3 via complementary PH-like domains to set cell-surface expression.","evidence":"Co-immunoprecipitation, domain mapping, and surface-expression assays","pmids":["15744307"],"confidence":"High","gaps":["Structural basis of the PH-PH interaction not resolved","Whether PLC-γ1 acts catalytically or as scaffold here not separated"]},{"year":2008,"claim":"Identified RACK1 as a scaffold determining TRPC3 plasma membrane localization and linking it to IP3R-dependent Ca2+ release, and mapped specific N-terminal residues mediating the interaction.","evidence":"Site-directed mutagenesis, co-IP, surface expression, siRNA, and Ca2+ imaging in HEK293 cells","pmids":["18755685"],"confidence":"High","gaps":["In vivo relevance of RACK1 scaffolding not tested","Single cell system"]},{"year":2008,"claim":"Defined the erythropoietin-responsive activation pathway, showing Epo activates TRPC3 via PLC-γ and IP3R interactions requiring Tyr-226 and C-terminal residues that distinguish TRPC3 from TRPC6.","evidence":"Co-IP, mutagenesis, Ca2+ imaging, and siRNA in HEK293T and primary erythroid precursors; later chimera/mutagenesis mapping of TRP-domain and AMPK-binding determinants","pmids":["18276585","21757714"],"confidence":"High","gaps":["Direct DAG vs PLC-γ scaffold contribution not fully separated","Role of AMPK binding in vivo not established"]},{"year":2009,"claim":"Linked TRPC3 channel gating to neuronal development and disease through a gain-of-function S4-S5 linker mutation causing Purkinje cell loss and ataxia.","evidence":"ENU mutagenesis screen with electrophysiology, histology, and behavioral testing in moonwalker mice","pmids":["19351902"],"confidence":"High","gaps":["Cell-autonomous vs network contribution to ataxia not fully resolved","Downstream signaling causing dendritic defect undefined"]},{"year":2009,"claim":"Provided a selective pharmacological tool (Pyr3) that binds TRPC3 directly, enabling clean dissection of TRPC3 function across systems.","evidence":"Electrophysiology, SAR studies, and photoaffinity labeling in DT40 cells and cardiomyocytes","pmids":["19289841"],"confidence":"High","gaps":["Selectivity over other TRPC members in all cell types not exhaustively mapped"]},{"year":2010,"claim":"Established TRPC3 as a dual-function protein acting both as a Ca2+ channel and a scaffold for PKCβ to sustain ERK signaling.","evidence":"TRPC3-deficient DT40 B cells with electrophysiology, live PKCβ-GFP imaging, co-IP, and ERK assays","pmids":["20179100"],"confidence":"High","gaps":["Whether scaffolding requires ion conduction not separated here","B-cell-specific vs general relevance unclear"]},{"year":2016,"claim":"Defined the TRPC3-Nox2 axis, showing mutual protein stabilization and that disrupting the complex eliminates ROS output while preserving Ca2+ influx, mechanistically separating TRPC3's scaffold and channel roles in cardiac pathology.","evidence":"Co-IP, proteasome inhibition, C-terminal minipeptide competition, ROS/Ca2+ assays, and pressure-overload mouse model; extended to GEF-H1/RhoA fibrotic signaling","pmids":["27833156","27991560"],"confidence":"High","gaps":["Structural basis of TRPC3-Nox2 binding not resolved","Whether the same complex operates outside heart not established"]},{"year":2017,"claim":"Demonstrated the in vivo therapeutic relevance of decoupling TRPC3 from Nox2, showing a C-terminal minipeptide blocks doxorubicin-induced cardiomyocyte atrophy without affecting hypoxic stress.","evidence":"Cardiomyocyte-specific transgenic minipeptide expression, Nox2 co-IP, morphometry, and echocardiography in mice; β-arrestin-1-biased AT1R signaling shown to recruit TRPC3/PLCγ for catecholamine secretion","pmids":["28768915","28181498"],"confidence":"High","gaps":["Long-term efficacy and off-target effects not assessed","Generality across cardiotoxic agents partly defined"]},{"year":2018,"claim":"Provided the molecular architecture of TRPC3, revealing a tetrameric two-layer assembly with ankyrin repeats and a C-terminal coiled-coil mediating inter-subunit contacts.","evidence":"Single-particle cryo-EM at 4.4 Å with inhibitor-bound TRPC6 as functional reference","pmids":["29700422"],"confidence":"High","gaps":["Resolution limited; lipid and DAG densities not fully resolved","Gating conformational states not captured"]},{"year":2022,"claim":"Integrated lipid regulation and subcellular targeting, defining three PI(4,5)P2-dependent regulatory modes and an FFAT-VAPB interaction that recruits TRPC3 to ER/PM junctions.","evidence":"Electrophysiology, lipid-binding-site and FFAT-motif mutagenesis, and VAPB-TRPC3 co-IP","pmids":["35416932"],"confidence":"High","gaps":["Dynamics of junctional recruitment in native cells not visualized","Interplay with PLC-γ1/RACK1 trafficking pathways not integrated"]},{"year":2022,"claim":"Expanded TRPC3's role to ER/mitochondria Ca2+ regulation, showing it negatively regulates IP3R-mediated Ca2+ transfer to influence senescence and metabolism.","evidence":"TRPC3 re-expression in senescent fibroblasts, mitochondrial Ca2+ imaging, OCR, and xenograft assays","pmids":["35177596"],"confidence":"Medium","gaps":["Direct vs indirect inhibition of IP3R not established","Single-lab finding"]},{"year":null,"claim":"How TRPC3's ion-conduction and scaffolding functions are coordinated at distinct subcellular sites, and how its lipid, kinase, and trafficking regulators are integrated into a unified gating model, remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No high-resolution structure of a DAG- or PI(4,5)P2-bound open state","Quantitative relationship between scaffold-dependent ROS signaling and channel-dependent Ca2+ signaling in vivo unclear","Mechanism unifying PLC-γ1, RACK1, and VAPB/FFAT trafficking inputs undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[0,1,2,19]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[20]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[15,16]},{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[16]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[7,11,15,25]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[20]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[28]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,18,30]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[3,13,32]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[16,26]},{"term_id":"R-HSA-397014","term_label":"Muscle contraction","supporting_discovery_ids":[22,25,36]}],"complexes":[],"partners":["PLCG1","RACK1","CYBB","NCX1","PKCB","ARHGEF2","VAPB","TRPC1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q13507","full_name":"Short transient receptor potential channel 3","aliases":["Transient receptor protein 3","TRP-3","hTrp-3","hTrp3"],"length_aa":921,"mass_kda":105.5,"function":"Forms a receptor-activated non-selective calcium permeant cation channel (PubMed:29726814, PubMed:30139744, PubMed:35051376, PubMed:9417057, PubMed:9930701, PubMed:10611319) Forms a receptor-activated non-selective calcium permeant cation channel. May be operated by a phosphatidylinositol second messenger system activated by receptor tyrosine kinases or G-protein coupled receptors","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q13507/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TRPC3","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TRPC3","total_profiled":1310},"omim":[{"mim_id":"616410","title":"SPINOCEREBELLAR ATAXIA 41; SCA41","url":"https://www.omim.org/entry/616410"},{"mim_id":"612489","title":"RING FINGER PROTEIN 24; RNF24","url":"https://www.omim.org/entry/612489"},{"mim_id":"610277","title":"ORAI CALCIUM RELEASE-ACTIVATED CALCIUM MODULATOR 1; ORAI1","url":"https://www.omim.org/entry/610277"},{"mim_id":"606665","title":"OPSIN 4; OPN4","url":"https://www.omim.org/entry/606665"},{"mim_id":"605921","title":"STROMAL INTERACTION MOLECULE 1; STIM1","url":"https://www.omim.org/entry/605921"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"brain","ntpm":4.7},{"tissue":"pituitary gland","ntpm":7.0},{"tissue":"retina","ntpm":3.6}],"url":"https://www.proteinatlas.org/search/TRPC3"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q13507","domains":[{"cath_id":"1.25.40.20","chopping":"27-204","consensus_level":"medium","plddt":84.3217,"start":27,"end":204},{"cath_id":"-","chopping":"220-282_291-304","consensus_level":"medium","plddt":87.656,"start":220,"end":304},{"cath_id":"-","chopping":"335-548","consensus_level":"medium","plddt":84.8838,"start":335,"end":548},{"cath_id":"-","chopping":"556-684","consensus_level":"high","plddt":90.8498,"start":556,"end":684}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13507","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q13507-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q13507-F1-predicted_aligned_error_v6.png","plddt_mean":78.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TRPC3","jax_strain_url":"https://www.jax.org/strain/search?query=TRPC3"},"sequence":{"accession":"Q13507","fasta_url":"https://rest.uniprot.org/uniprotkb/Q13507.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q13507/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13507"}},"corpus_meta":[{"pmid":"9930701","id":"PMC_9930701","title":"Direct activation of human TRPC6 and TRPC3 channels by diacylglycerol.","date":"1999","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/9930701","citation_count":1280,"is_preprint":false},{"pmid":"19289841","id":"PMC_19289841","title":"Selective and direct inhibition of TRPC3 channels underlies biological activities of a pyrazole compound.","date":"2009","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/19289841","citation_count":315,"is_preprint":false},{"pmid":"10677043","id":"PMC_10677043","title":"Activation of a TRPC3-dependent cation current through the neurotrophin BDNF.","date":"1999","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/10677043","citation_count":288,"is_preprint":false},{"pmid":"12765690","id":"PMC_12765690","title":"The TRPC3/6/7 subfamily of cation channels.","date":"2003","source":"Cell calcium","url":"https://pubmed.ncbi.nlm.nih.gov/12765690","citation_count":187,"is_preprint":false},{"pmid":"16537542","id":"PMC_16537542","title":"TRPC3 and TRPC4 associate to form a redox-sensitive cation channel. Evidence for expression of native TRPC3-TRPC4 heteromeric channels in endothelial cells.","date":"2006","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16537542","citation_count":177,"is_preprint":false},{"pmid":"19351902","id":"PMC_19351902","title":"A point mutation in TRPC3 causes abnormal Purkinje cell development and cerebellar ataxia in moonwalker mice.","date":"2009","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/19351902","citation_count":171,"is_preprint":false},{"pmid":"12970363","id":"PMC_12970363","title":"N-linked protein glycosylation is a major determinant for basal TRPC3 and TRPC6 channel activity.","date":"2003","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12970363","citation_count":166,"is_preprint":false},{"pmid":"24453217","id":"PMC_24453217","title":"Combined TRPC3 and TRPC6 blockade by selective small-molecule or genetic deletion inhibits pathological cardiac hypertrophy.","date":"2014","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/24453217","citation_count":165,"is_preprint":false},{"pmid":"15744307","id":"PMC_15744307","title":"Phospholipase Cgamma1 controls surface expression of TRPC3 through an intermolecular PH domain.","date":"2005","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/15744307","citation_count":156,"is_preprint":false},{"pmid":"29700422","id":"PMC_29700422","title":"Structure of the receptor-activated human TRPC6 and TRPC3 ion channels.","date":"2018","source":"Cell research","url":"https://pubmed.ncbi.nlm.nih.gov/29700422","citation_count":155,"is_preprint":false},{"pmid":"12606542","id":"PMC_12606542","title":"Signaling mechanism for receptor-activated canonical transient receptor potential 3 (TRPC3) channels.","date":"2003","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12606542","citation_count":140,"is_preprint":false},{"pmid":"14983059","id":"PMC_14983059","title":"Regulation of canonical transient receptor potential isoform 3 (TRPC3) channel by protein kinase G.","date":"2004","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/14983059","citation_count":135,"is_preprint":false},{"pmid":"22724068","id":"PMC_22724068","title":"TRPC3 and TRPC6 are essential for normal mechanotransduction in subsets of sensory neurons and cochlear hair cells.","date":"2012","source":"Open biology","url":"https://pubmed.ncbi.nlm.nih.gov/22724068","citation_count":134,"is_preprint":false},{"pmid":"15604128","id":"PMC_15604128","title":"TRPC3 mediates pyrimidine receptor-induced depolarization of cerebral arteries.","date":"2004","source":"American journal of physiology. Heart and circulatory physiology","url":"https://pubmed.ncbi.nlm.nih.gov/15604128","citation_count":129,"is_preprint":false},{"pmid":"15971081","id":"PMC_15971081","title":"The diacylgylcerol-sensitive TRPC3/6/7 subfamily of cation channels: functional characterization and physiological relevance.","date":"2005","source":"Pflugers Archiv : European journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/15971081","citation_count":126,"is_preprint":false},{"pmid":"11466302","id":"PMC_11466302","title":"Expression of functional receptor-coupled TRPC3 channels in DT40 triple receptor InsP3 knockout cells.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11466302","citation_count":125,"is_preprint":false},{"pmid":"12736256","id":"PMC_12736256","title":"TRPC3 mediates T-cell receptor-dependent calcium entry in human T-lymphocytes.","date":"2003","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12736256","citation_count":109,"is_preprint":false},{"pmid":"15533987","id":"PMC_15533987","title":"Negative regulation of TRPC3 channels by protein kinase C-mediated phosphorylation of serine 712.","date":"2004","source":"Molecular pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/15533987","citation_count":108,"is_preprint":false},{"pmid":"28181498","id":"PMC_28181498","title":"Arrestin-biased AT1R agonism induces acute catecholamine secretion through TRPC3 coupling.","date":"2017","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/28181498","citation_count":103,"is_preprint":false},{"pmid":"27833156","id":"PMC_27833156","title":"TRPC3 positively regulates reactive oxygen species driving maladaptive cardiac remodeling.","date":"2016","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/27833156","citation_count":93,"is_preprint":false},{"pmid":"15672411","id":"PMC_15672411","title":"Receptor-operated Ca2+ entry mediated by TRPC3/TRPC6 proteins in rat prostate smooth muscle (PS1) cell line.","date":"2005","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/15672411","citation_count":92,"is_preprint":false},{"pmid":"21215279","id":"PMC_21215279","title":"TRP expression pattern and the functional importance of TRPC3 in primary human T-cells.","date":"2011","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/21215279","citation_count":89,"is_preprint":false},{"pmid":"20932261","id":"PMC_20932261","title":"Pharmacological modulation of diacylglycerol-sensitive TRPC3/6/7 channels.","date":"2011","source":"Current pharmaceutical biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/20932261","citation_count":87,"is_preprint":false},{"pmid":"15909153","id":"PMC_15909153","title":"Functional characterization and physiological relevance of the TRPC3/6/7 subfamily of cation channels.","date":"2005","source":"Naunyn-Schmiedeberg's archives of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/15909153","citation_count":81,"is_preprint":false},{"pmid":"16484216","id":"PMC_16484216","title":"Functional coupling between TRPC3 and RyR1 regulates the expressions of key triadic proteins.","date":"2006","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16484216","citation_count":79,"is_preprint":false},{"pmid":"25631581","id":"PMC_25631581","title":"TRPC3 contributes to regulation of cardiac contractility and arrhythmogenesis by dynamic interaction with NCX1.","date":"2015","source":"Cardiovascular research","url":"https://pubmed.ncbi.nlm.nih.gov/25631581","citation_count":74,"is_preprint":false},{"pmid":"27991560","id":"PMC_27991560","title":"TRPC3-GEF-H1 axis mediates pressure overload-induced cardiac fibrosis.","date":"2016","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/27991560","citation_count":71,"is_preprint":false},{"pmid":"20881130","id":"PMC_20881130","title":"Transient receptor potential canonical 3 (TRPC3) mediates thrombin-induced astrocyte activation and upregulates its own expression in cortical astrocytes.","date":"2010","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/20881130","citation_count":71,"is_preprint":false},{"pmid":"17699666","id":"PMC_17699666","title":"TrpC3/C7 and Slo2.1 are molecular targets for metabotropic glutamate receptor signaling in rat striatal cholinergic interneurons.","date":"2007","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/17699666","citation_count":65,"is_preprint":false},{"pmid":"25892961","id":"PMC_25892961","title":"Brain-derived neurotrophic factor regulates TRPC3/6 channels and protects against myocardial infarction in rodents.","date":"2015","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/25892961","citation_count":64,"is_preprint":false},{"pmid":"19502552","id":"PMC_19502552","title":"Inhibition of TRPC1/TRPC3 by PKG contributes to NO-mediated vasorelaxation.","date":"2009","source":"American journal of physiology. Heart and circulatory physiology","url":"https://pubmed.ncbi.nlm.nih.gov/19502552","citation_count":64,"is_preprint":false},{"pmid":"16280289","id":"PMC_16280289","title":"Increased transient receptor potential channel TRPC3 expression in spontaneously hypertensive rats.","date":"2005","source":"American journal of hypertension","url":"https://pubmed.ncbi.nlm.nih.gov/16280289","citation_count":62,"is_preprint":false},{"pmid":"30636880","id":"PMC_30636880","title":"LncRNA SNHG5 promotes growth and invasion in melanoma by regulating the miR-26a-5p/TRPC3 pathway.","date":"2018","source":"OncoTargets and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/30636880","citation_count":61,"is_preprint":false},{"pmid":"35177596","id":"PMC_35177596","title":"TRPC3 shapes the ER-mitochondria Ca2+ transfer characterizing tumour-promoting senescence.","date":"2022","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/35177596","citation_count":59,"is_preprint":false},{"pmid":"28768915","id":"PMC_28768915","title":"TRPC3-Nox2 complex mediates doxorubicin-induced myocardial atrophy.","date":"2017","source":"JCI insight","url":"https://pubmed.ncbi.nlm.nih.gov/28768915","citation_count":59,"is_preprint":false},{"pmid":"20179100","id":"PMC_20179100","title":"Ca2+ influx and protein scaffolding via TRPC3 sustain PKCbeta and ERK activation in B cells.","date":"2010","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/20179100","citation_count":59,"is_preprint":false},{"pmid":"18215135","id":"PMC_18215135","title":"TRPC3-interacting triadic proteins in skeletal muscle.","date":"2008","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/18215135","citation_count":57,"is_preprint":false},{"pmid":"25513972","id":"PMC_25513972","title":"TRPC3 channels critically regulate hippocampal excitability and contextual fear memory.","date":"2014","source":"Behavioural brain research","url":"https://pubmed.ncbi.nlm.nih.gov/25513972","citation_count":55,"is_preprint":false},{"pmid":"28645743","id":"PMC_28645743","title":"Role of TRPC3 and TRPC6 channels in the myocardial response to stretch: Linking physiology and pathophysiology.","date":"2017","source":"Progress in biophysics and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/28645743","citation_count":53,"is_preprint":false},{"pmid":"31003514","id":"PMC_31003514","title":"TRPC3 Regulates the Proliferation and Apoptosis Resistance of Triple Negative Breast Cancer Cells through the TRPC3/RASA4/MAPK Pathway.","date":"2019","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/31003514","citation_count":52,"is_preprint":false},{"pmid":"30037143","id":"PMC_30037143","title":"TRPC3 as a Target of Novel Therapeutic Interventions.","date":"2018","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/30037143","citation_count":51,"is_preprint":false},{"pmid":"24965271","id":"PMC_24965271","title":"Contribution of TRPC3 to store-operated calcium entry and inflammatory transductions in primary nociceptors.","date":"2014","source":"Molecular pain","url":"https://pubmed.ncbi.nlm.nih.gov/24965271","citation_count":51,"is_preprint":false},{"pmid":"16529812","id":"PMC_16529812","title":"Calcium store contents control the expression of TRPC1, TRPC3 and TRPV6 proteins in LNCaP prostate cancer cell line.","date":"2006","source":"Cell calcium","url":"https://pubmed.ncbi.nlm.nih.gov/16529812","citation_count":51,"is_preprint":false},{"pmid":"31486767","id":"PMC_31486767","title":"TRPC3 is a major contributor to functional heterogeneity of cerebellar Purkinje cells.","date":"2019","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/31486767","citation_count":50,"is_preprint":false},{"pmid":"21441586","id":"PMC_21441586","title":"mGluR1/TRPC3-mediated Synaptic Transmission and Calcium Signaling in Mammalian Central Neurons.","date":"2011","source":"Cold Spring Harbor perspectives in biology","url":"https://pubmed.ncbi.nlm.nih.gov/21441586","citation_count":49,"is_preprint":false},{"pmid":"29387339","id":"PMC_29387339","title":"miR-26a inhibits atherosclerosis progression by targeting TRPC3.","date":"2018","source":"Cell & bioscience","url":"https://pubmed.ncbi.nlm.nih.gov/29387339","citation_count":48,"is_preprint":false},{"pmid":"23899746","id":"PMC_23899746","title":"TRPC3 regulates release of brain-derived neurotrophic factor from human airway smooth muscle.","date":"2013","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/23899746","citation_count":48,"is_preprint":false},{"pmid":"19447651","id":"PMC_19447651","title":"Enhanced expression of STIM1/Orai1 and TRPC3 in platelets from patients with type 2 diabetes mellitus.","date":"2009","source":"Blood cells, molecules & diseases","url":"https://pubmed.ncbi.nlm.nih.gov/19447651","citation_count":43,"is_preprint":false},{"pmid":"16331690","id":"PMC_16331690","title":"Protein kinase C can inhibit TRPC3 channels indirectly via stimulating protein kinase G.","date":"2006","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/16331690","citation_count":42,"is_preprint":false},{"pmid":"21493700","id":"PMC_21493700","title":"TRPC3 channel contributes to nitric oxide release: significance during normoxia and hypoxia-reoxygenation.","date":"2011","source":"Cardiovascular research","url":"https://pubmed.ncbi.nlm.nih.gov/21493700","citation_count":42,"is_preprint":false},{"pmid":"18755685","id":"PMC_18755685","title":"TRPC3 controls agonist-stimulated intracellular Ca2+ release by mediating the interaction between inositol 1,4,5-trisphosphate receptor and RACK1.","date":"2008","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18755685","citation_count":42,"is_preprint":false},{"pmid":"18787184","id":"PMC_18787184","title":"Involvement of native TRPC3 proteins in ATP-dependent expression of VCAM-1 and monocyte adherence in coronary artery endothelial cells.","date":"2008","source":"Arteriosclerosis, thrombosis, and vascular biology","url":"https://pubmed.ncbi.nlm.nih.gov/18787184","citation_count":42,"is_preprint":false},{"pmid":"24905090","id":"PMC_24905090","title":"Calcium sensing receptor modulates extracellular calcium entry and proliferation via TRPC3/6 channels in cultured human mesangial cells.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24905090","citation_count":40,"is_preprint":false},{"pmid":"26219954","id":"PMC_26219954","title":"Proarrhythmic effect of sustained EPAC activation on TRPC3/4 in rat ventricular cardiomyocytes.","date":"2015","source":"Journal of molecular and cellular cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/26219954","citation_count":40,"is_preprint":false},{"pmid":"23068106","id":"PMC_23068106","title":"Different binding property of STIM1 and its novel splice variant STIM1L to Orai1, TRPC3, and TRPC6 channels.","date":"2012","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/23068106","citation_count":40,"is_preprint":false},{"pmid":"30962089","id":"PMC_30962089","title":"Trimetazidine prevents diabetic cardiomyopathy by inhibiting Nox2/TRPC3-induced oxidative stress.","date":"2019","source":"Journal of pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/30962089","citation_count":39,"is_preprint":false},{"pmid":"18276585","id":"PMC_18276585","title":"TRPC3 is the erythropoietin-regulated calcium channel in human erythroid cells.","date":"2008","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18276585","citation_count":38,"is_preprint":false},{"pmid":"28936433","id":"PMC_28936433","title":"TRPC3 Channels in Cardiac Fibrosis.","date":"2017","source":"Frontiers in cardiovascular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/28936433","citation_count":37,"is_preprint":false},{"pmid":"23095462","id":"PMC_23095462","title":"Role of TRPC1 and TRPC3 channels in contraction and relaxation of mouse thoracic aorta.","date":"2012","source":"Journal of vascular research","url":"https://pubmed.ncbi.nlm.nih.gov/23095462","citation_count":37,"is_preprint":false},{"pmid":"25467798","id":"PMC_25467798","title":"Activation of calcium-sensing receptor increases TRPC3/6 expression in T lymphocyte in sepsis.","date":"2014","source":"Molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/25467798","citation_count":35,"is_preprint":false},{"pmid":"35869392","id":"PMC_35869392","title":"PLAA suppresses ovarian cancer metastasis via METTL3-mediated m6A modification of TRPC3 mRNA.","date":"2022","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/35869392","citation_count":33,"is_preprint":false},{"pmid":"24797279","id":"PMC_24797279","title":"The Moonwalker mouse: new insights into TRPC3 function, cerebellar development, and ataxia.","date":"2014","source":"Cerebellum (London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/24797279","citation_count":33,"is_preprint":false},{"pmid":"15203106","id":"PMC_15203106","title":"TRPC3-like protein and vitamin D receptor mediate 1alpha,25(OH)2D3-induced SOC influx in muscle cells.","date":"2004","source":"The international journal of biochemistry & cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/15203106","citation_count":32,"is_preprint":false},{"pmid":"21811471","id":"PMC_21811471","title":"Upregulated TRPC3 and Downregulated TRPC1 Channel Expression during Hypertension is Associated with Increased Vascular Contractility in Rat.","date":"2011","source":"Frontiers in physiology","url":"https://pubmed.ncbi.nlm.nih.gov/21811471","citation_count":32,"is_preprint":false},{"pmid":"21684255","id":"PMC_21684255","title":"Impairment of survival signaling and efferocytosis in TRPC3-deficient macrophages.","date":"2011","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/21684255","citation_count":32,"is_preprint":false},{"pmid":"28790356","id":"PMC_28790356","title":"TRPC6 counteracts TRPC3-Nox2 protein complex leading to attenuation of hyperglycemia-induced heart failure in mice.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/28790356","citation_count":32,"is_preprint":false},{"pmid":"28716528","id":"PMC_28716528","title":"Treatment with TREK1 and TRPC3/6 ion channel inhibitors upregulates microRNA expression in a mouse model of chronic mild stress.","date":"2017","source":"Neuroscience letters","url":"https://pubmed.ncbi.nlm.nih.gov/28716528","citation_count":31,"is_preprint":false},{"pmid":"33707208","id":"PMC_33707208","title":"Progesterone receptor isoform B regulates the Oxtr-Plcl2-Trpc3 pathway to suppress uterine contractility.","date":"2021","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/33707208","citation_count":30,"is_preprint":false},{"pmid":"34311033","id":"PMC_34311033","title":"TRPC3 promotes tumorigenesis of gastric cancer via the CNB2/GSK3β/NFATc2 signaling pathway.","date":"2021","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/34311033","citation_count":30,"is_preprint":false},{"pmid":"31680473","id":"PMC_31680473","title":"Protective mechanism of SIRT1 on Hcy-induced atrial fibrosis mediated by TRPC3.","date":"2019","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/31680473","citation_count":30,"is_preprint":false},{"pmid":"26520460","id":"PMC_26520460","title":"The contribution of TRPC1, TRPC3, TRPC5 and TRPC6 to touch and hearing.","date":"2015","source":"Neuroscience letters","url":"https://pubmed.ncbi.nlm.nih.gov/26520460","citation_count":29,"is_preprint":false},{"pmid":"25031020","id":"PMC_25031020","title":"Reduced endoplasmic reticulum stress-induced apoptosis and impaired unfolded protein response in TRPC3-deficient M1 macrophages.","date":"2014","source":"American journal of physiology. Cell physiology","url":"https://pubmed.ncbi.nlm.nih.gov/25031020","citation_count":29,"is_preprint":false},{"pmid":"35416932","id":"PMC_35416932","title":"TRPC3 channel gating by lipids requires localization at the ER/PM junctions defined by STIM1.","date":"2022","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/35416932","citation_count":28,"is_preprint":false},{"pmid":"27899482","id":"PMC_27899482","title":"Transient Receptor Potential Canonical 3 (TRPC3) Channels Are Required for Hypothalamic Glucose Detection and Energy Homeostasis.","date":"2016","source":"Diabetes","url":"https://pubmed.ncbi.nlm.nih.gov/27899482","citation_count":28,"is_preprint":false},{"pmid":"29435486","id":"PMC_29435486","title":"Transient Receptor Potential Channels TRPM4 and TRPC3 Critically Contribute to Respiratory Motor Pattern Formation but not Rhythmogenesis in Rodent Brainstem Circuits.","date":"2018","source":"eNeuro","url":"https://pubmed.ncbi.nlm.nih.gov/29435486","citation_count":28,"is_preprint":false},{"pmid":"31241172","id":"PMC_31241172","title":"Ibudilast attenuates doxorubicin-induced cytotoxicity by suppressing formation of TRPC3 channel and NADPH oxidase 2 protein complexes.","date":"2019","source":"British journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/31241172","citation_count":28,"is_preprint":false},{"pmid":"25213992","id":"PMC_25213992","title":"Upregulation and Diverse Roles of TRPC3 and TRPC6 in Synaptic Reorganization of the Mossy Fiber Pathway in Temporal Lobe Epilepsy.","date":"2014","source":"Molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/25213992","citation_count":28,"is_preprint":false},{"pmid":"25908616","id":"PMC_25908616","title":"The mutant Moonwalker TRPC3 channel links calcium signaling to lipid metabolism in the developing cerebellum.","date":"2015","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/25908616","citation_count":27,"is_preprint":false},{"pmid":"31278358","id":"PMC_31278358","title":"TRPC3-Nox2 axis mediates nutritional deficiency-induced cardiomyocyte atrophy.","date":"2019","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/31278358","citation_count":26,"is_preprint":false},{"pmid":"31543348","id":"PMC_31543348","title":"TRPC3 deficiency attenuates high salt-induced cardiac hypertrophy by alleviating cardiac mitochondrial dysfunction.","date":"2019","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/31543348","citation_count":26,"is_preprint":false},{"pmid":"21757714","id":"PMC_21757714","title":"The transient receptor potential (TRP) channel TRPC3 TRP domain and AMP-activated protein kinase binding site are required for TRPC3 activation by erythropoietin.","date":"2011","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21757714","citation_count":26,"is_preprint":false},{"pmid":"28636132","id":"PMC_28636132","title":"TRPC1- and TRPC3-dependent Ca2+ signaling in mouse cortical astrocytes affects injury-evoked astrogliosis in vivo.","date":"2017","source":"Glia","url":"https://pubmed.ncbi.nlm.nih.gov/28636132","citation_count":26,"is_preprint":false},{"pmid":"24756703","id":"PMC_24756703","title":"TRPC3: a multifunctional signaling molecule.","date":"2014","source":"Handbook of experimental pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/24756703","citation_count":25,"is_preprint":false},{"pmid":"34409942","id":"PMC_34409942","title":"TRPC3 and NALCN channels drive pacemaking in substantia nigra dopaminergic neurons.","date":"2021","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/34409942","citation_count":25,"is_preprint":false},{"pmid":"23852583","id":"PMC_23852583","title":"Adaptive responses of TRPC1 and TRPC3 during skeletal muscle atrophy and regrowth.","date":"2014","source":"Muscle & nerve","url":"https://pubmed.ncbi.nlm.nih.gov/23852583","citation_count":24,"is_preprint":false},{"pmid":"17217051","id":"PMC_17217051","title":"TRPC3: a multifunctional, pore-forming signalling molecule.","date":"2007","source":"Handbook of experimental pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/17217051","citation_count":24,"is_preprint":false},{"pmid":"19074769","id":"PMC_19074769","title":"TRPC3 activation by erythropoietin is modulated by TRPC6.","date":"2008","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19074769","citation_count":23,"is_preprint":false},{"pmid":"23602965","id":"PMC_23602965","title":"Chronic oxidative stress modulates TRPC3 and TRPM2 channel expression and function in rat primary cortical neurons: relevance to the pathophysiology of bipolar disorder.","date":"2013","source":"Brain research","url":"https://pubmed.ncbi.nlm.nih.gov/23602965","citation_count":23,"is_preprint":false},{"pmid":"35179226","id":"PMC_35179226","title":"Inhibition of TRPC3 channels by a novel pyrazole compound confers antiseizure effects.","date":"2022","source":"Epilepsia","url":"https://pubmed.ncbi.nlm.nih.gov/35179226","citation_count":22,"is_preprint":false},{"pmid":"26512833","id":"PMC_26512833","title":"TRPC3 regulates the automaticity of embryonic stem cell-derived cardiomyocytes.","date":"2015","source":"International journal of cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/26512833","citation_count":22,"is_preprint":false},{"pmid":"20644344","id":"PMC_20644344","title":"TRPC3 cation channel plays an important role in proliferation and differentiation of skeletal muscle myoblasts.","date":"2010","source":"Experimental & molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/20644344","citation_count":22,"is_preprint":false},{"pmid":"26041382","id":"PMC_26041382","title":"TRPC3-dependent synaptic transmission in central mammalian neurons.","date":"2015","source":"Journal of molecular medicine (Berlin, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/26041382","citation_count":21,"is_preprint":false},{"pmid":"25859221","id":"PMC_25859221","title":"The involvement of TRPC3 channels in sinoatrial arrhythmias.","date":"2015","source":"Frontiers in physiology","url":"https://pubmed.ncbi.nlm.nih.gov/25859221","citation_count":21,"is_preprint":false},{"pmid":"19882163","id":"PMC_19882163","title":"TRPC3 ion channel subunit immunolocalization in the cochlea.","date":"2009","source":"Histochemistry and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/19882163","citation_count":21,"is_preprint":false},{"pmid":"28764936","id":"PMC_28764936","title":"TRPC3- and ETB receptor-mediated PI3K/AKT activation induces vasogenic edema formation following status epilepticus.","date":"2017","source":"Brain research","url":"https://pubmed.ncbi.nlm.nih.gov/28764936","citation_count":20,"is_preprint":false},{"pmid":"26952156","id":"PMC_26952156","title":"Nicotine Induces Cardiomyocyte Hypertrophy Through TRPC3-Mediated Ca2+/NFAT Signalling Pathway.","date":"2015","source":"The Canadian journal of cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/26952156","citation_count":19,"is_preprint":false},{"pmid":"20229053","id":"PMC_20229053","title":"Developmental regulation of TRPC3 ion channel expression in the mouse cochlea.","date":"2010","source":"Histochemistry and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/20229053","citation_count":19,"is_preprint":false},{"pmid":"21321808","id":"PMC_21321808","title":"Candidate screening of the TRPC3 gene in cerebellar ataxia.","date":"2011","source":"Cerebellum (London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/21321808","citation_count":19,"is_preprint":false},{"pmid":"21996795","id":"PMC_21996795","title":"Expression and association of TRPC1 with TRPC3 during skeletal myogenesis.","date":"2011","source":"Muscle & nerve","url":"https://pubmed.ncbi.nlm.nih.gov/21996795","citation_count":18,"is_preprint":false},{"pmid":"18602703","id":"PMC_18602703","title":"Autoantibodies against TRPC3 and ryanodine receptor in myasthenia gravis.","date":"2008","source":"Journal of neuroimmunology","url":"https://pubmed.ncbi.nlm.nih.gov/18602703","citation_count":18,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":52043,"output_tokens":9516,"usd":0.149434,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":19732,"output_tokens":5180,"usd":0.11408,"stage2_stop_reason":"end_turn"},"total_usd":0.263514,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1999,\n      \"finding\": \"TRPC3 (and TRPC6) are directly activated by diacylglycerol in a membrane-delimited, protein kinase C-independent manner, establishing them as second-messenger-operated cation channels downstream of phospholipase C.\",\n      \"method\": \"Electrophysiology (patch clamp) in heterologous expression system; pharmacological dissection\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct in vitro electrophysiological reconstitution, PKC-independent mechanism established by pharmacology, replicated across multiple subsequent studies\",\n      \"pmids\": [\"9930701\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Receptor-mediated activation of TRPC3 in intact cells proceeds via diacylglycerol produced by phospholipase C, independently of G proteins, protein kinase C, or IP3; receptor agonists and exogenous DAG are non-additive and DAG metabolism inhibition slows reversal, confirming DAG as the proximal activator.\",\n      \"method\": \"Ca2+ imaging, electrophysiology, pharmacological inhibitors, and InsP3R-knockout DT40 cell system\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal methods in intact cells plus genetic (InsP3R-KO) confirmation, consistent with earlier reconstitution data\",\n      \"pmids\": [\"12606542\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"TRPC3 channels are activated independently of IP3 receptors through DAG production from either PLC-γ or PLC-β, demonstrated in DT40 cells with all three InsP3R genes deleted.\",\n      \"method\": \"Expression of TRPC3 in DT40 InsP3R triple-knockout cells; Ca2+ imaging; pharmacological inhibition of PLC\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis using triple-KO cell line with pharmacological controls, directly tests the IP3R-coupling model\",\n      \"pmids\": [\"11466302\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"TRPC3 is highly enriched in CNS neurons and co-localizes temporally and spatially with TrkB; activation of TrkB by BDNF leads to a PLC-dependent, nonselective cation conductance in pontine neurons that requires TRPC3.\",\n      \"method\": \"Immunohistochemistry, electrophysiology in brain slices, antisense knockdown\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — antisense knockdown of endogenous TRPC3 in primary neurons with electrophysiological readout, replicated in multiple neuron types\",\n      \"pmids\": [\"10677043\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"N-linked glycosylation at a single extracellular site (e2 loop) is a major determinant of TRPC3 constitutive activity; TRPC3 is monoglycosylated compared to dually glycosylated TRPC6, and engineering an additional glycosylation site into TRPC3 markedly reduces its basal activity.\",\n      \"method\": \"Site-directed mutagenesis of NxS/T glycosylation sites, immunoblotting, electrophysiology, Ca2+ imaging in HEK293 cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis combined with electrophysiology and fluorescence imaging; reciprocal gain- and loss-of-function in single lab\",\n      \"pmids\": [\"12970363\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Protein kinase G (PKG) directly phosphorylates TRPC3 at Thr-11 and Ser-263, inhibiting store-operated Ca2+ influx mediated by TRPC3; point mutations T11A and S263Q abolish cGMP/PKG-dependent inhibition.\",\n      \"method\": \"In vitro PKG phosphorylation assay on purified TRPC3 protein; site-directed mutagenesis; Ca2+ imaging in HEK293 cells stably expressing PKG\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay with purified protein plus mutagenesis and functional Ca2+ readout in cells\",\n      \"pmids\": [\"14983059\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Protein kinase C negatively regulates TRPC3 by phosphorylating Ser-712; a S712A mutant is resistant to PMA-induced inhibition and shows greater receptor-stimulated Ca2+ entry than wild-type TRPC3.\",\n      \"method\": \"Site-directed mutagenesis, in vivo phosphorylation assay, electrophysiology, Ca2+ imaging in HEK293 cells\",\n      \"journal\": \"Molecular pharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis combined with phosphorylation assay and functional readouts; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"15533987\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"PLC-γ1 binds to TRPC3 via complementary partial pleckstrin homology (PH) domains; the partial PH domain of PLC-γ1 interacts with a PH-like domain in TRPC3 to mediate lipid binding and control cell-surface expression of TRPC3.\",\n      \"method\": \"Co-immunoprecipitation, domain mapping, gestalt PH-domain algorithm, cell-surface expression assay\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus domain mapping with functional surface-expression readout in single lab; published in Nature\",\n      \"pmids\": [\"15744307\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"TRPC3 and TRPC4 associate to form a redox-sensitive heteromeric cation channel in endothelial cells; FRET shows close proximity between TRPC4 N-terminus and TRPC3 C-terminus; co-expression generates channels with distinct biophysical properties; dominant-negative TRPC4 suppresses TRPC3-related currents in both HEK293 and native endothelial cells.\",\n      \"method\": \"Co-immunoprecipitation, FRET, electrophysiology, dominant-negative suppression in HEK293 and porcine aortic endothelial cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — four independent lines of evidence including FRET, co-IP, electrophysiology, and dominant-negative in native cells\",\n      \"pmids\": [\"16537542\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"TRPC3 interacts functionally with RyR1 to regulate gain of SR Ca2+ release during excitation-contraction coupling in skeletal muscle; knockdown of TRPC3 reduces RyR1 Ca2+ release channel activity and alters expression of triadic proteins (TRPC1, calsequestrin, triadin, junctophilin 1).\",\n      \"method\": \"Retroviral siRNA knockdown in primary skeletal myoblasts; Mn2+ influx, Ca2+ imaging with Fura-2 and Fluo-4; immunoblot\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean knockdown with multiple functional readouts; indirect functional coupling (no direct binding shown)\",\n      \"pmids\": [\"16484216\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"TRPC3 interacts directly with six triadic proteins (TRPC1, JP2, homer, mitsugumin 29, calreticulin, calmodulin) in skeletal muscle in a Ca2+-independent manner, but shows no direct interaction with RyR1; TRPC1 is identified as a physical link between TRPC3 and RyR1.\",\n      \"method\": \"MALDI-TOF MS of cross-linked triadic vesicles, co-immunoprecipitation from primary mouse myotubes\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS identification plus co-IP; direct binding confirmed for six partners; absence of TRPC3-RyR1 direct interaction is a confirmed negative\",\n      \"pmids\": [\"18215135\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"TRPC3 interacts with RACK1 via N-terminal residues Glu-232, Asp-233, Glu-240, and Glu-244; this interaction determines plasma membrane localization of TRPC3 and controls IP3R-RACK1 association and IP3-dependent intracellular Ca2+ release.\",\n      \"method\": \"Site-directed mutagenesis of TRPC3, co-immunoprecipitation, surface expression assay, Ca2+ imaging in HEK293 cells, siRNA knockdown\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — mutagenesis identifying specific residues, co-IP, surface expression, and functional Ca2+ readouts in same study\",\n      \"pmids\": [\"18755685\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Erythropoietin regulates Ca2+ influx through TRPC3 via a PLC-γ-mediated process requiring interaction of PLC-γ and IP3R with TRPC3; TRPC3 Tyr-226 is critical for Epo-dependent activation; C-terminal domains (residues 671–746) confer Epo-responsiveness distinguishing TRPC3 from TRPC6.\",\n      \"method\": \"Co-immunoprecipitation, site-directed mutagenesis of TRPC3 (Y226F, IP3R-binding domain mutants), Ca2+ imaging in HEK293T cells and primary erythroid precursors, siRNA knockdown of PLC-γ\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — mutagenesis + co-IP + functional Ca2+ readouts + primary cell validation in single study\",\n      \"pmids\": [\"18276585\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"A gain-of-function point mutation T635A in the S4-S5 linker of TRPC3 causes altered channel gating, impairs Purkinje cell dendritic arbor development, and leads to Purkinje cell loss and cerebellar ataxia in moonwalker mice.\",\n      \"method\": \"ENU mutagenesis screen, Sanger sequencing, electrophysiology, histology, behavioral testing in mice\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — identified causative mutation with electrophysiological characterization and histological/behavioral phenotyping; replicated in subsequent studies\",\n      \"pmids\": [\"19351902\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"The pyrazole compound Pyr3 selectively and directly inhibits TRPC3 channels; the trichloroacrylic amide group confers TRPC3 selectivity; direct action on TRPC3 protein confirmed by photoaffinity labeling.\",\n      \"method\": \"Electrophysiology, structure-activity relationship studies, photoaffinity labeling, Ca2+ imaging in DT40 B cells and cardiomyocytes\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — photoaffinity labeling directly demonstrates binding to TRPC3 protein; SAR studies plus functional assays; replicated widely\",\n      \"pmids\": [\"19289841\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"TRPC3 functions both as a Ca2+-permeable channel and a protein scaffold for PKCβ at the plasma membrane; TRPC3 deficiency impairs DAG-activated cation currents and sustained PKCβ translocation to the plasma membrane, reducing ERK activation after BCR stimulation; TRPC3 directly associates with PKCβ.\",\n      \"method\": \"TRPC3-deficient DT40 B cells, electrophysiology, live-cell imaging of PKCβ-GFP, co-immunoprecipitation, ERK activation assay\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic deficiency model, electrophysiology, live imaging, and co-IP; multiple orthogonal methods in one study\",\n      \"pmids\": [\"20179100\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"TRPC3 physically interacts with NADPH oxidase 2 (Nox2) at specific C-terminal sites, protecting Nox2 from proteasomal degradation and amplifying Ca2+-dependent Nox2 activation; Nox2 also stabilizes TRPC3 protein; disruption of the TRPC3-Nox2 complex by a C-terminal polypeptide abolishes TRPC3-regulated ROS production without affecting TRPC3-mediated Ca2+ influx.\",\n      \"method\": \"Co-immunoprecipitation, proteasome inhibitor experiments, C-terminal minipeptide competition, ROS assays, Ca2+ imaging, pressure overload mouse model\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — co-IP + peptide disruption dissecting ROS from Ca2+ functions + in vivo mouse model; replicated in multiple subsequent publications\",\n      \"pmids\": [\"27833156\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"TRPC3 mediates RhoA activation and fibrotic responses through interaction with microtubule-associated GEF-H1; inhibition of TRPC3 attenuates GEF-H1 activation and Rho-mediated fibrosis in pressure-overloaded hearts; Nox2 inhibition also attenuates stretch-induced GEF-H1 activation, placing it downstream of TRPC3-Nox2.\",\n      \"method\": \"Proteomic analysis, co-immunoprecipitation, pharmacological TRPC3 inhibition, pressure overload mouse model, RhoA activity assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomic identification plus co-IP plus in vivo model with pharmacological inhibition; consistent with established TRPC3-Nox2 axis\",\n      \"pmids\": [\"27991560\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TRPC3 mediates acute catecholamine secretion triggered by the β-arrestin-1-biased AT1R agonist TRV120027; TRV120027 promotes recruitment of TRPC3 or PLCγ to the AT1R-β-arrestin-1 signaling complex; blocking β-arrestin-1–PLCγ interaction with a TAT-P1 peptide abolishes TRPC3 activation.\",\n      \"method\": \"Co-immunoprecipitation, TAT-P1 peptide competition, Ca2+ imaging, catecholamine secretion assay, β-arrestin chimera replacement\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP + peptide disruption + functional readout; mechanistic dissection of arrestin-PLCγ-TRPC3 axis\",\n      \"pmids\": [\"28181498\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Cryo-EM structure of human TRPC3 at 4.4 Å resolution reveals a tetrameric two-layer architecture with N-terminal ankyrin repeats and C-terminal coiled-coil contributing to inter-subunit contacts; the related TRPC6 structure with inhibitor BTDM shows the inhibitor wedges between S5-S6 pore domain and voltage sensor-like domain.\",\n      \"method\": \"Single-particle cryo-electron microscopy\",\n      \"journal\": \"Cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure at near-atomic resolution providing molecular architecture; includes inhibitor-bound TRPC6 as functional reference\",\n      \"pmids\": [\"29700422\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PI(4,5)P2 regulates TRPC3 through three independent modes: (1) PLC-dependent hydrolysis generates DAG that interacts with lipid-binding site 2 in the pore; (2) PI(4,5)P2 interacts with lipid site 1 to inhibit TRPC3 opening and gate DAG access to site 2; (3) PI(4,5)P2 is required for receptor-stimulated changes in pore ionic selectivity. TRPC3 requires recruitment to ER/PM junctions via an FFAT motif that interacts with ER-resident VAPB.\",\n      \"method\": \"Electrophysiology, mutagenesis of lipid-binding sites, identification and mutation of FFAT motif, co-immunoprecipitation of VAPB-TRPC3\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple mutagenesis experiments with defined lipid-binding sites, FFAT-VAPB interaction, and electrophysiological functional validation in one rigorous study\",\n      \"pmids\": [\"35416932\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"PKC-mediated inhibition of TRPC3 is partly indirect, operating through PKG in vascular endothelial cells; PKG inhibitors significantly reduce PMA-induced inhibition of TRPC3 in native endothelial cells, linking the two kinase pathways.\",\n      \"method\": \"Ca2+ imaging, pharmacological inhibitors of PKC and PKG, point mutants T11A-S263Q, endothelial cell experiments\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis plus pharmacological dissection in both overexpression and native cells; single lab but two cell systems\",\n      \"pmids\": [\"16331690\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"TRPC3 mediates UTP-induced (pyrimidine receptor-activated) depolarization and constriction of cerebral artery smooth muscle cells, but not myogenic (pressure-induced) responses; TRPC6 mediates myogenic depolarization, indicating differential regulation of closely related channels by receptor vs. mechanical stimuli.\",\n      \"method\": \"Antisense oligodeoxynucleotide knockdown of TRPC3 or TRPC6 in cerebral arteries; patch clamp; pressure myography\",\n      \"journal\": \"American journal of physiology. Heart and circulatory physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — antisense knockdown with electrophysiological and contractility readouts in native tissue; single lab\",\n      \"pmids\": [\"15604128\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"TRPC3 and TRPC1 are co-expressed in vascular smooth muscle cells and co-immunoprecipitate; both contribute to UTP-stimulated nonselective cation currents; NO/cGMP/PKG signaling inhibits TRPC1/TRPC3 and this inhibition contributes to NO-mediated vasorelaxation.\",\n      \"method\": \"Co-immunoprecipitation, intracellular antibody blockade in patch clamp, PKG inhibitor (KT5823), vessel myograph relaxation assay in rat carotid artery\",\n      \"journal\": \"American journal of physiology. Heart and circulatory physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus functional patch clamp with intracellular antibody blockade and vessel pharmacology; single lab\",\n      \"pmids\": [\"19502552\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"TRPC3 and TRPC6 are required for normal mechanosensation: loss of TRPC3 alone shifts rapidly-adapting mechanosensitive currents to intermediate-adapting currents in DRG neurons; double TRPC3/TRPC6 KO silences half of RA-current neurons, impairs light touch, and causes hearing and vestibular deficits; co-expression of TRPC3 and TRPC6 in sensory neuron cell lines induces FM1-43-sensitive mechanically gated currents.\",\n      \"method\": \"Single and double KO mice, patch clamp of DRG neurons and cochlear hair cells, behavioral testing, heterologous co-expression\",\n      \"journal\": \"Open biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic double-KO with multiple electrophysiological and behavioral readouts plus heterologous reconstitution\",\n      \"pmids\": [\"22724068\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TRPC3 co-localizes with NCX1 in cardiomyocytes and forms a micro/nanodomain; TRPC3 activation by GSK1702934A or angiotensin II promotes NCX1 currents and transiently causes spatial uncoupling of TRPC3 from NCX1, leading to Ca2+ overload and arrhythmogenesis; pro-arrhythmic effects are prevented by NCX inhibition.\",\n      \"method\": \"Immunocytochemistry colocalization, electrophysiology in TRPC3-overexpressing cardiomyocytes, Langendorff heart preparation, NCX inhibitor 3',4'-dichlorobenzamil\",\n      \"journal\": \"Cardiovascular research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — colocalization plus functional electrophysiology and pharmacology in transgenic mouse model; single lab\",\n      \"pmids\": [\"25631581\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TRPC3 acts as a negative regulator of IP3 receptor-mediated Ca2+ release at the ER/mitochondria interface; TRPC3 downregulation in senescent fibroblasts leads to elevated cytosolic/mitochondrial Ca2+ oscillations, increased mitochondrial Ca2+ load, and elevated OXPHOS; re-expression of TRPC3 in senescent cells reduces mitochondrial Ca2+ and promotes escape from oncogene-induced senescence.\",\n      \"method\": \"TRPC3 re-expression in senescent cells, mitochondrial Ca2+ imaging, OCR measurement, xenograft tumor assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — rescue experiment with functional Ca2+ and metabolic readouts plus in vivo tumor model; single lab\",\n      \"pmids\": [\"35177596\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TRPC3-Nox2 complex mediates doxorubicin-induced myocardial atrophy; cardiomyocyte-specific expression of TRPC3 C-terminal minipeptide inhibits TRPC3-Nox2 coupling and suppresses doxorubicin-induced cardiomyocyte size reduction and LV dysfunction without reducing hypoxic stress.\",\n      \"method\": \"Cardiomyocyte-specific transgenic minipeptide expression, Nox2 co-IP, morphometric analysis, echocardiography in mice\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic minipeptide dissection of complex in vivo, consistent with established TRPC3-Nox2 mechanism across multiple papers\",\n      \"pmids\": [\"28768915\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"TRPC3 TRP domain residues (DDKPS) and the distal C-terminal AMP-activated protein kinase (AMPK) binding site are required for erythropoietin-induced TRPC3 activation and cytoskeletal association/plasma membrane insertion; chimeric TRPC6 channels gain Epo responsiveness when given TRPC3 TRP domain plus C2/AMPK site.\",\n      \"method\": \"Site-directed mutagenesis, TRPC3/TRPC6 chimeric channels, Ca2+ imaging, cell surface expression assay in HEK293T and primary erythroblasts\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — systematic mutagenesis and chimera approach; functional readouts in heterologous and primary cells; single lab\",\n      \"pmids\": [\"21757714\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Thrombin upregulates TRPC3 protein in cortical astrocytes via PAR-1/ERK/JNK/NF-κB signaling; TRPC3-mediated Ca2+ signaling feeds forward to further increase its own expression; TRPC3 knockdown inhibits thrombin-induced astrocyte morphological changes, S100B upregulation, and proliferation.\",\n      \"method\": \"siRNA knockdown, pharmacological inhibitors (Pyr3, BAPTA-AM, 2-APB), Western blot, immunofluorescence, proliferation assay in cortical astrocytes and in vivo PAR-1 agonist injection\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with multiple functional endpoints plus in vivo confirmation; single lab\",\n      \"pmids\": [\"20881130\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TRPC3 regulates triple-negative breast cancer cell proliferation and apoptosis resistance through a TRPC3-RASA4-MAPK signaling cascade: Ca2+ influx through TRPC3 sustains RASA4 localization on the plasma membrane, where it suppresses Ras-MAPK pathway activation.\",\n      \"method\": \"Subcellular fractionation, Western blot, Pyr3 pharmacology, dominant-negative TRPC3, proliferation and apoptosis assays, RASA4 membrane localization assay\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — subcellular fractionation plus pharmacological and dominant-negative manipulations with functional readouts; single lab\",\n      \"pmids\": [\"31003514\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TRPC3-Nox2 complex mediates nutritional deficiency-induced cardiomyocyte atrophy through extracellular ATP/P2Y2 receptor signaling; knockdown of either TRPC3 or Nox2 suppresses ATP-mediated Nox2 protein increases, ROS production, and cardiomyocyte atrophy.\",\n      \"method\": \"siRNA knockdown of TRPC3 and Nox2, co-IP, ROS measurement, cardiomyocyte size measurement in neonatal rat cardiomyocytes\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus knockdown of both components with functional readouts; consistent with established TRPC3-Nox2 axis\",\n      \"pmids\": [\"31278358\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TRPC3 and NALCN together form sustained inward currents responsible for the slow depolarization driving pacemaking in nigral dopamine neurons; specific blockade of TRPC3 abolishes pacemaking, but TRPC3 KO mice retain normal pacemaking due to compensatory NALCN upregulation.\",\n      \"method\": \"Pharmacological TRPC3 blockade, TRPC3 KO and NALCN blockade in mouse substantia nigra slice electrophysiology; NALCN mRNA and protein quantification\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — pharmacological and genetic dissection with electrophysiology; compensatory mechanism verified by molecular quantification\",\n      \"pmids\": [\"34409942\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"STIM1L, a splice variant of STIM1, binds more abundantly to TRPC3 (and TRPC6) than canonical STIM1, and tends to suppress receptor-operated Ca2+ entry via TRPC3 and TRPC6 more strongly than STIM1; co-immunoprecipitation confirms STIM1L-TRPC3 physical association.\",\n      \"method\": \"Co-immunoprecipitation, Ca2+ imaging (thapsigargin and endothelin-1 protocols), HEK293 cells stably expressing ETA receptor\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP plus functional Ca2+ measurements; single lab\",\n      \"pmids\": [\"23068106\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Progesterone receptor isoform B (PGR-B) suppresses uterine contractility by downregulating TRPC3 (and OXTR) while upregulating PLCL2, reducing oxytocin signaling; PGR-B overexpression in smooth muscle results in prolonged gestation and labor dystocia.\",\n      \"method\": \"Transgenic mice overexpressing PGR-A or PGR-B in smooth muscle, uterine RNA sequencing, ex vivo and in vivo contractility measurement, CRISPRa-based functional assay of PLCL1/2\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transcriptomic + CRISPRa functional validation + in vivo transgenic model; TRPC3 is one of multiple downstream targets identified\",\n      \"pmids\": [\"33707208\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"TRPC3 channels are required for hypothalamic glucose detection: whole-body and MBH-specific TRPC3-deficient mice show impaired anorectic response to intracerebroventricular glucose, blunted insulin secretion response to intracarotid glucose, and reduced Ca2+ responses to glucose in mediobasal hypothalamus GE neurons.\",\n      \"method\": \"Constitutive and conditional TRPC3 KO mice, in vivo food intake and insulin secretion assays, in vitro Ca2+ imaging of freshly dissociated MBH neurons, pharmacological inhibition with Pyr3\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO plus pharmacology plus in vitro Ca2+ imaging; multiple endpoints and two KO models\",\n      \"pmids\": [\"27899482\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TRPC3 is located at T-tubules of embryonic stem cell-derived cardiomyocytes; TRPC3 current contributes to diastolic depolarization (phase 4), local Ca2+ release, and NCX current; reducing TRPC3 current decreases action potential rate and RyR2/phospholamban phosphorylation.\",\n      \"method\": \"Immunocytochemistry, whole-cell patch clamp, confocal Ca2+ imaging, combined current and voltage clamp, dominant negative TRPC3 construct in mESC-derived cardiomyocytes\",\n      \"journal\": \"International journal of cardiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — electrophysiology plus Ca2+ imaging with dominant-negative construct; single lab, multiple readouts\",\n      \"pmids\": [\"26512833\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PLAA inhibits METTL3 expression via ubiquitin-mediated degradation; METTL3 stabilizes TRPC3 mRNA via m6A modification; reduced TRPC3 expression following PLAA upregulation decreases intracellular Ca2+ and suppresses ovarian cancer cell migration and invasion.\",\n      \"method\": \"Co-IP/ubiquitin assay, m6A-seq/RIP, CRISPR KO, Ca2+ imaging, xenograft orthotopic mouse model\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic chain from PLAA to METTL3 to m6A-TRPC3 mRNA established by co-IP and m6A assays with functional in vivo readout; single lab\",\n      \"pmids\": [\"35869392\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TRPC3 is a receptor-operated, non-selective cation channel that is directly and PKC-independently activated by diacylglycerol generated downstream of PLC-coupled receptors; its activity is negatively regulated by PKC phosphorylation at Ser-712 and by PKG phosphorylation at Thr-11/Ser-263; channel localization to the plasma membrane is controlled by PLC-γ1 via complementary PH-like domains and by RACK1-mediated scaffolding; PI(4,5)P2 regulates TRPC3 through dual lipid-binding sites and requires FFAT-VAPB interaction for ER/PM junction targeting; beyond ion conduction, TRPC3 acts as a protein scaffold (for PKCβ, Nox2, NCX1, GEF-H1) and as a positive regulator of ROS production by stabilizing Nox2 against proteasomal degradation, thereby encoding Ca2+-influx signals into ROS-mediated cardiac fibrosis and atrophy; in the cerebellum, a gain-of-function T635A mutation disrupts Purkinje cell dendritic development and causes ataxia, while normal TRPC3 supports mGluR1-mediated slow EPSPs and Purkinje cell heterogeneity; in the substantia nigra, TRPC3 and NALCN together drive dopamine neuron pacemaking; in erythroid cells, TRPC3 is activated by erythropoietin through PLCγ and IP3R interactions requiring specific TRP-domain and C-terminal AMPK-binding site residues.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TRPC3 is a receptor-operated, non-selective cation channel that translates phospholipase C signaling into Ca2+ influx and downstream cellular responses across neurons, cardiomyocytes, smooth muscle, and erythroid cells [#0, #1]. It is directly and PKC-independently gated by diacylglycerol produced when PLC-coupled receptors are engaged, with receptor agonists and exogenous DAG acting non-additively and independently of G proteins, IP3, or IP3 receptors [#0, #1, #2]. Channel gating and surface expression are tuned by post-translational and lipid inputs: N-linked glycosylation of an extracellular e2 loop restrains constitutive activity [#4], PKC phosphorylation at Ser-712 and PKG phosphorylation at Thr-11/Ser-263 inhibit the channel [#5, #6], and PI(4,5)P2 regulates opening through dual pore lipid-binding sites that also gate DAG access, while an FFAT motif recruits TRPC3 to ER/PM junctions via ER-resident VAPB [#20]. Cryo-EM defines a tetrameric two-layer architecture with N-terminal ankyrin repeats and a C-terminal coiled-coil forming inter-subunit contacts [#19]. Surface localization is controlled by PLC-\\u03b31 through complementary PH-like domains and by N-terminal RACK1 interactions [#7, #11]. Beyond ion conduction, TRPC3 functions as a protein scaffold, directly binding PKC\\u03b2, NADPH oxidase 2 (Nox2), NCX1, and GEF-H1, and it stabilizes Nox2 against proteasomal degradation to amplify Ca2+-dependent ROS production that drives cardiac fibrosis and atrophy [#15, #16, #17, #25, #27]. Physiologically, TRPC3 supports BDNF/TrkB-evoked cation currents in neurons [#3], partners with NALCN to drive nigral dopamine neuron pacemaking [#32], mediates mechanosensation together with TRPC6 [#24], and contributes to hypothalamic glucose sensing [#35]; a gain-of-function T635A mutation in the S4-S5 linker disrupts Purkinje cell dendritic development and causes cerebellar ataxia in moonwalker mice [#13].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Established the activation logic of TRPC3 by showing it is gated directly by diacylglycerol independently of PKC, defining it as a second-messenger-operated channel downstream of PLC rather than a store-operated channel.\",\n      \"evidence\": \"Patch-clamp electrophysiology with pharmacological dissection in heterologous cells; antisense knockdown linking endogenous TRPC3 to TrkB/BDNF-evoked currents in pontine neurons\",\n      \"pmids\": [\"9930701\", \"10677043\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the molecular DAG-binding site\", \"Native receptor pathways coupling to TRPC3 not yet enumerated\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Resolved whether IP3 receptors are required for TRPC3 gating, showing activation proceeds via DAG from either PLC-\\u03b3 or PLC-\\u03b2 in cells lacking all IP3 receptors.\",\n      \"evidence\": \"Expression of TRPC3 in DT40 InsP3R triple-knockout cells with Ca2+ imaging and PLC inhibition; confirmed in intact cells with InsP3R-KO controls\",\n      \"pmids\": [\"11466302\", \"12606542\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not exclude context-dependent IP3R modulation in other cell types\", \"Proximal lipid-channel interaction not structurally defined\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Identified extracellular glycosylation as a determinant of basal channel activity, explaining why TRPC3 is more constitutively active than TRPC6.\",\n      \"evidence\": \"Site-directed mutagenesis of NxS/T sites with immunoblotting and electrophysiology in HEK293 cells\",\n      \"pmids\": [\"12970363\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which glycosylation alters gating not defined\", \"Single-lab result\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Defined kinase-mediated negative regulation, showing PKG (Thr-11/Ser-263) and PKC (Ser-712) directly phosphorylate and inhibit TRPC3.\",\n      \"evidence\": \"In vitro kinase assays on purified TRPC3, phospho-site mutagenesis, and Ca2+ imaging in HEK293 cells\",\n      \"pmids\": [\"14983059\", \"15533987\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Crosstalk between the two kinase inputs not yet ordered\", \"Physiological triggers of each phosphorylation in native cells unclear\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Showed channel trafficking is controlled by lipid-domain protein interactions, with PLC-\\u03b31 binding TRPC3 via complementary PH-like domains to set cell-surface expression.\",\n      \"evidence\": \"Co-immunoprecipitation, domain mapping, and surface-expression assays\",\n      \"pmids\": [\"15744307\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the PH-PH interaction not resolved\", \"Whether PLC-\\u03b31 acts catalytically or as scaffold here not separated\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identified RACK1 as a scaffold determining TRPC3 plasma membrane localization and linking it to IP3R-dependent Ca2+ release, and mapped specific N-terminal residues mediating the interaction.\",\n      \"evidence\": \"Site-directed mutagenesis, co-IP, surface expression, siRNA, and Ca2+ imaging in HEK293 cells\",\n      \"pmids\": [\"18755685\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance of RACK1 scaffolding not tested\", \"Single cell system\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defined the erythropoietin-responsive activation pathway, showing Epo activates TRPC3 via PLC-\\u03b3 and IP3R interactions requiring Tyr-226 and C-terminal residues that distinguish TRPC3 from TRPC6.\",\n      \"evidence\": \"Co-IP, mutagenesis, Ca2+ imaging, and siRNA in HEK293T and primary erythroid precursors; later chimera/mutagenesis mapping of TRP-domain and AMPK-binding determinants\",\n      \"pmids\": [\"18276585\", \"21757714\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct DAG vs PLC-\\u03b3 scaffold contribution not fully separated\", \"Role of AMPK binding in vivo not established\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Linked TRPC3 channel gating to neuronal development and disease through a gain-of-function S4-S5 linker mutation causing Purkinje cell loss and ataxia.\",\n      \"evidence\": \"ENU mutagenesis screen with electrophysiology, histology, and behavioral testing in moonwalker mice\",\n      \"pmids\": [\"19351902\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell-autonomous vs network contribution to ataxia not fully resolved\", \"Downstream signaling causing dendritic defect undefined\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Provided a selective pharmacological tool (Pyr3) that binds TRPC3 directly, enabling clean dissection of TRPC3 function across systems.\",\n      \"evidence\": \"Electrophysiology, SAR studies, and photoaffinity labeling in DT40 cells and cardiomyocytes\",\n      \"pmids\": [\"19289841\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Selectivity over other TRPC members in all cell types not exhaustively mapped\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Established TRPC3 as a dual-function protein acting both as a Ca2+ channel and a scaffold for PKC\\u03b2 to sustain ERK signaling.\",\n      \"evidence\": \"TRPC3-deficient DT40 B cells with electrophysiology, live PKC\\u03b2-GFP imaging, co-IP, and ERK assays\",\n      \"pmids\": [\"20179100\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether scaffolding requires ion conduction not separated here\", \"B-cell-specific vs general relevance unclear\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined the TRPC3-Nox2 axis, showing mutual protein stabilization and that disrupting the complex eliminates ROS output while preserving Ca2+ influx, mechanistically separating TRPC3's scaffold and channel roles in cardiac pathology.\",\n      \"evidence\": \"Co-IP, proteasome inhibition, C-terminal minipeptide competition, ROS/Ca2+ assays, and pressure-overload mouse model; extended to GEF-H1/RhoA fibrotic signaling\",\n      \"pmids\": [\"27833156\", \"27991560\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of TRPC3-Nox2 binding not resolved\", \"Whether the same complex operates outside heart not established\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrated the in vivo therapeutic relevance of decoupling TRPC3 from Nox2, showing a C-terminal minipeptide blocks doxorubicin-induced cardiomyocyte atrophy without affecting hypoxic stress.\",\n      \"evidence\": \"Cardiomyocyte-specific transgenic minipeptide expression, Nox2 co-IP, morphometry, and echocardiography in mice; \\u03b2-arrestin-1-biased AT1R signaling shown to recruit TRPC3/PLC\\u03b3 for catecholamine secretion\",\n      \"pmids\": [\"28768915\", \"28181498\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Long-term efficacy and off-target effects not assessed\", \"Generality across cardiotoxic agents partly defined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Provided the molecular architecture of TRPC3, revealing a tetrameric two-layer assembly with ankyrin repeats and a C-terminal coiled-coil mediating inter-subunit contacts.\",\n      \"evidence\": \"Single-particle cryo-EM at 4.4 \\u00c5 with inhibitor-bound TRPC6 as functional reference\",\n      \"pmids\": [\"29700422\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Resolution limited; lipid and DAG densities not fully resolved\", \"Gating conformational states not captured\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Integrated lipid regulation and subcellular targeting, defining three PI(4,5)P2-dependent regulatory modes and an FFAT-VAPB interaction that recruits TRPC3 to ER/PM junctions.\",\n      \"evidence\": \"Electrophysiology, lipid-binding-site and FFAT-motif mutagenesis, and VAPB-TRPC3 co-IP\",\n      \"pmids\": [\"35416932\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Dynamics of junctional recruitment in native cells not visualized\", \"Interplay with PLC-\\u03b31/RACK1 trafficking pathways not integrated\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Expanded TRPC3's role to ER/mitochondria Ca2+ regulation, showing it negatively regulates IP3R-mediated Ca2+ transfer to influence senescence and metabolism.\",\n      \"evidence\": \"TRPC3 re-expression in senescent fibroblasts, mitochondrial Ca2+ imaging, OCR, and xenograft assays\",\n      \"pmids\": [\"35177596\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect inhibition of IP3R not established\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TRPC3's ion-conduction and scaffolding functions are coordinated at distinct subcellular sites, and how its lipid, kinase, and trafficking regulators are integrated into a unified gating model, remains unresolved.\",\n      \"evidence\": null,\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No high-resolution structure of a DAG- or PI(4,5)P2-bound open state\", \"Quantitative relationship between scaffold-dependent ROS signaling and channel-dependent Ca2+ signaling in vivo unclear\", \"Mechanism unifying PLC-\\u03b31, RACK1, and VAPB/FFAT trafficking inputs undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [0, 1, 2, 19]},\n      {\"term_id\": \"GO:0005262\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [20]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [15, 16]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [16]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [7, 11, 15, 25]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [20]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [28]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 18, 30]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [3, 13, 32]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [16, 26]},\n      {\"term_id\": \"R-HSA-397014\", \"supporting_discovery_ids\": [22, 25, 36]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"PLCG1\", \"RACK1\", \"CYBB\", \"NCX1\", \"PKCB\", \"ARHGEF2\", \"VAPB\", \"TRPC1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}