Affinage

TRPC3

Short transient receptor potential channel 3 · UniProt Q13507

Length
921 aa
Mass
105.5 kDa
Annotated
2026-06-10
100 papers in source corpus 38 papers cited in narrative 38 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1999 High

    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

    PMID:10677043 PMID:9930701

    Open questions at the time
    • Did not resolve the molecular DAG-binding site
    • Native receptor pathways coupling to TRPC3 not yet enumerated
  2. 2001 High

    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

    PMID:11466302 PMID:12606542

    Open questions at the time
    • Did not exclude context-dependent IP3R modulation in other cell types
    • Proximal lipid-channel interaction not structurally defined
  3. 2003 High

    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

    PMID:12970363

    Open questions at the time
    • Mechanism by which glycosylation alters gating not defined
    • Single-lab result
  4. 2004 High

    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

    PMID:14983059 PMID:15533987

    Open questions at the time
    • Crosstalk between the two kinase inputs not yet ordered
    • Physiological triggers of each phosphorylation in native cells unclear
  5. 2005 High

    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

    PMID:15744307

    Open questions at the time
    • Structural basis of the PH-PH interaction not resolved
    • Whether PLC-γ1 acts catalytically or as scaffold here not separated
  6. 2008 High

    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

    PMID:18755685

    Open questions at the time
    • In vivo relevance of RACK1 scaffolding not tested
    • Single cell system
  7. 2008 High

    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

    PMID:18276585 PMID:21757714

    Open questions at the time
    • Direct DAG vs PLC-γ scaffold contribution not fully separated
    • Role of AMPK binding in vivo not established
  8. 2009 High

    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

    PMID:19351902

    Open questions at the time
    • Cell-autonomous vs network contribution to ataxia not fully resolved
    • Downstream signaling causing dendritic defect undefined
  9. 2009 High

    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

    PMID:19289841

    Open questions at the time
    • Selectivity over other TRPC members in all cell types not exhaustively mapped
  10. 2010 High

    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

    PMID:20179100

    Open questions at the time
    • Whether scaffolding requires ion conduction not separated here
    • B-cell-specific vs general relevance unclear
  11. 2016 High

    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

    PMID:27833156 PMID:27991560

    Open questions at the time
    • Structural basis of TRPC3-Nox2 binding not resolved
    • Whether the same complex operates outside heart not established
  12. 2017 High

    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

    PMID:28181498 PMID:28768915

    Open questions at the time
    • Long-term efficacy and off-target effects not assessed
    • Generality across cardiotoxic agents partly defined
  13. 2018 High

    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

    PMID:29700422

    Open questions at the time
    • Resolution limited; lipid and DAG densities not fully resolved
    • Gating conformational states not captured
  14. 2022 High

    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

    PMID:35416932

    Open questions at the time
    • Dynamics of junctional recruitment in native cells not visualized
    • Interplay with PLC-γ1/RACK1 trafficking pathways not integrated
  15. 2022 Medium

    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

    PMID:35177596

    Open questions at the time
    • Direct vs indirect inhibition of IP3R not established
    • Single-lab finding

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 4 GO:0060089 molecular transducer activity 2 GO:0060090 molecular adaptor activity 2 GO:0008289 lipid binding 1 GO:0140313 molecular sequestering activity 1
Localization
GO:0005886 plasma membrane 4 GO:0005783 endoplasmic reticulum 1 GO:0005856 cytoskeleton 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-112316 Neuronal System 3 R-HSA-397014 Muscle contraction 3 R-HSA-8953897 Cellular responses to stimuli 2
Partners
ARHGEF2CYBBNCX1PKCBPLCG1RACK1TRPC1VAPB

Evidence

Reading pass · 38 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 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. Electrophysiology (patch clamp) in heterologous expression system; pharmacological dissection Nature High 9930701
2003 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. Ca2+ imaging, electrophysiology, pharmacological inhibitors, and InsP3R-knockout DT40 cell system The Journal of biological chemistry High 12606542
2001 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. Expression of TRPC3 in DT40 InsP3R triple-knockout cells; Ca2+ imaging; pharmacological inhibition of PLC The Journal of biological chemistry High 11466302
1999 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. Immunohistochemistry, electrophysiology in brain slices, antisense knockdown Neuron High 10677043
2003 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. Site-directed mutagenesis of NxS/T glycosylation sites, immunoblotting, electrophysiology, Ca2+ imaging in HEK293 cells The Journal of biological chemistry High 12970363
2004 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. In vitro PKG phosphorylation assay on purified TRPC3 protein; site-directed mutagenesis; Ca2+ imaging in HEK293 cells stably expressing PKG Proceedings of the National Academy of Sciences of the United States of America High 14983059
2004 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. Site-directed mutagenesis, in vivo phosphorylation assay, electrophysiology, Ca2+ imaging in HEK293 cells Molecular pharmacology High 15533987
2005 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. Co-immunoprecipitation, domain mapping, gestalt PH-domain algorithm, cell-surface expression assay Nature High 15744307
2006 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. Co-immunoprecipitation, FRET, electrophysiology, dominant-negative suppression in HEK293 and porcine aortic endothelial cells The Journal of biological chemistry High 16537542
2006 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). Retroviral siRNA knockdown in primary skeletal myoblasts; Mn2+ influx, Ca2+ imaging with Fura-2 and Fluo-4; immunoblot The Journal of biological chemistry Medium 16484216
2008 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. MALDI-TOF MS of cross-linked triadic vesicles, co-immunoprecipitation from primary mouse myotubes The Biochemical journal Medium 18215135
2008 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. Site-directed mutagenesis of TRPC3, co-immunoprecipitation, surface expression assay, Ca2+ imaging in HEK293 cells, siRNA knockdown The Journal of biological chemistry High 18755685
2008 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. 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 The Journal of biological chemistry High 18276585
2009 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. ENU mutagenesis screen, Sanger sequencing, electrophysiology, histology, behavioral testing in mice Proceedings of the National Academy of Sciences of the United States of America High 19351902
2009 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. Electrophysiology, structure-activity relationship studies, photoaffinity labeling, Ca2+ imaging in DT40 B cells and cardiomyocytes Proceedings of the National Academy of Sciences of the United States of America High 19289841
2010 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. TRPC3-deficient DT40 B cells, electrophysiology, live-cell imaging of PKCβ-GFP, co-immunoprecipitation, ERK activation assay Journal of cell science High 20179100
2016 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. Co-immunoprecipitation, proteasome inhibitor experiments, C-terminal minipeptide competition, ROS assays, Ca2+ imaging, pressure overload mouse model Scientific reports High 27833156
2016 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. Proteomic analysis, co-immunoprecipitation, pharmacological TRPC3 inhibition, pressure overload mouse model, RhoA activity assays Scientific reports High 27991560
2017 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. Co-immunoprecipitation, TAT-P1 peptide competition, Ca2+ imaging, catecholamine secretion assay, β-arrestin chimera replacement Nature communications High 28181498
2018 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. Single-particle cryo-electron microscopy Cell research High 29700422
2022 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. Electrophysiology, mutagenesis of lipid-binding sites, identification and mutation of FFAT motif, co-immunoprecipitation of VAPB-TRPC3 The Journal of cell biology High 35416932
2006 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. Ca2+ imaging, pharmacological inhibitors of PKC and PKG, point mutants T11A-S263Q, endothelial cell experiments Journal of cellular physiology Medium 16331690
2004 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. Antisense oligodeoxynucleotide knockdown of TRPC3 or TRPC6 in cerebral arteries; patch clamp; pressure myography American journal of physiology. Heart and circulatory physiology Medium 15604128
2009 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. Co-immunoprecipitation, intracellular antibody blockade in patch clamp, PKG inhibitor (KT5823), vessel myograph relaxation assay in rat carotid artery American journal of physiology. Heart and circulatory physiology Medium 19502552
2012 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. Single and double KO mice, patch clamp of DRG neurons and cochlear hair cells, behavioral testing, heterologous co-expression Open biology High 22724068
2015 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. Immunocytochemistry colocalization, electrophysiology in TRPC3-overexpressing cardiomyocytes, Langendorff heart preparation, NCX inhibitor 3',4'-dichlorobenzamil Cardiovascular research Medium 25631581
2022 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. TRPC3 re-expression in senescent cells, mitochondrial Ca2+ imaging, OCR measurement, xenograft tumor assay Nature communications Medium 35177596
2017 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. Cardiomyocyte-specific transgenic minipeptide expression, Nox2 co-IP, morphometric analysis, echocardiography in mice JCI insight High 28768915
2011 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. Site-directed mutagenesis, TRPC3/TRPC6 chimeric channels, Ca2+ imaging, cell surface expression assay in HEK293T and primary erythroblasts The Journal of biological chemistry Medium 21757714
2010 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. siRNA knockdown, pharmacological inhibitors (Pyr3, BAPTA-AM, 2-APB), Western blot, immunofluorescence, proliferation assay in cortical astrocytes and in vivo PAR-1 agonist injection The Journal of neuroscience Medium 20881130
2019 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. Subcellular fractionation, Western blot, Pyr3 pharmacology, dominant-negative TRPC3, proliferation and apoptosis assays, RASA4 membrane localization assay Cancers Medium 31003514
2019 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. siRNA knockdown of TRPC3 and Nox2, co-IP, ROS measurement, cardiomyocyte size measurement in neonatal rat cardiomyocytes Scientific reports Medium 31278358
2021 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. Pharmacological TRPC3 blockade, TRPC3 KO and NALCN blockade in mouse substantia nigra slice electrophysiology; NALCN mRNA and protein quantification eLife High 34409942
2012 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. Co-immunoprecipitation, Ca2+ imaging (thapsigargin and endothelin-1 protocols), HEK293 cells stably expressing ETA receptor Biochemical and biophysical research communications Medium 23068106
2021 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. 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 Proceedings of the National Academy of Sciences of the United States of America Medium 33707208
2016 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. 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 Diabetes High 27899482
2019 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. Immunocytochemistry, whole-cell patch clamp, confocal Ca2+ imaging, combined current and voltage clamp, dominant negative TRPC3 construct in mESC-derived cardiomyocytes International journal of cardiology Medium 26512833
2022 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. Co-IP/ubiquitin assay, m6A-seq/RIP, CRISPR KO, Ca2+ imaging, xenograft orthotopic mouse model Oncogene Medium 35869392

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1999 Direct activation of human TRPC6 and TRPC3 channels by diacylglycerol. Nature 1280 9930701
2009 Selective and direct inhibition of TRPC3 channels underlies biological activities of a pyrazole compound. Proceedings of the National Academy of Sciences of the United States of America 315 19289841
1999 Activation of a TRPC3-dependent cation current through the neurotrophin BDNF. Neuron 288 10677043
2003 The TRPC3/6/7 subfamily of cation channels. Cell calcium 187 12765690
2006 TRPC3 and TRPC4 associate to form a redox-sensitive cation channel. Evidence for expression of native TRPC3-TRPC4 heteromeric channels in endothelial cells. The Journal of biological chemistry 177 16537542
2009 A point mutation in TRPC3 causes abnormal Purkinje cell development and cerebellar ataxia in moonwalker mice. Proceedings of the National Academy of Sciences of the United States of America 171 19351902
2003 N-linked protein glycosylation is a major determinant for basal TRPC3 and TRPC6 channel activity. The Journal of biological chemistry 166 12970363
2014 Combined TRPC3 and TRPC6 blockade by selective small-molecule or genetic deletion inhibits pathological cardiac hypertrophy. Proceedings of the National Academy of Sciences of the United States of America 165 24453217
2005 Phospholipase Cgamma1 controls surface expression of TRPC3 through an intermolecular PH domain. Nature 156 15744307
2018 Structure of the receptor-activated human TRPC6 and TRPC3 ion channels. Cell research 155 29700422
2003 Signaling mechanism for receptor-activated canonical transient receptor potential 3 (TRPC3) channels. The Journal of biological chemistry 140 12606542
2004 Regulation of canonical transient receptor potential isoform 3 (TRPC3) channel by protein kinase G. Proceedings of the National Academy of Sciences of the United States of America 135 14983059
2012 TRPC3 and TRPC6 are essential for normal mechanotransduction in subsets of sensory neurons and cochlear hair cells. Open biology 134 22724068
2004 TRPC3 mediates pyrimidine receptor-induced depolarization of cerebral arteries. American journal of physiology. Heart and circulatory physiology 129 15604128
2005 The diacylgylcerol-sensitive TRPC3/6/7 subfamily of cation channels: functional characterization and physiological relevance. Pflugers Archiv : European journal of physiology 126 15971081
2001 Expression of functional receptor-coupled TRPC3 channels in DT40 triple receptor InsP3 knockout cells. The Journal of biological chemistry 125 11466302
2003 TRPC3 mediates T-cell receptor-dependent calcium entry in human T-lymphocytes. The Journal of biological chemistry 109 12736256
2004 Negative regulation of TRPC3 channels by protein kinase C-mediated phosphorylation of serine 712. Molecular pharmacology 108 15533987
2017 Arrestin-biased AT1R agonism induces acute catecholamine secretion through TRPC3 coupling. Nature communications 103 28181498
2016 TRPC3 positively regulates reactive oxygen species driving maladaptive cardiac remodeling. Scientific reports 93 27833156
2005 Receptor-operated Ca2+ entry mediated by TRPC3/TRPC6 proteins in rat prostate smooth muscle (PS1) cell line. Journal of cellular physiology 92 15672411
2011 TRP expression pattern and the functional importance of TRPC3 in primary human T-cells. Biochimica et biophysica acta 89 21215279
2011 Pharmacological modulation of diacylglycerol-sensitive TRPC3/6/7 channels. Current pharmaceutical biotechnology 87 20932261
2005 Functional characterization and physiological relevance of the TRPC3/6/7 subfamily of cation channels. Naunyn-Schmiedeberg's archives of pharmacology 81 15909153
2006 Functional coupling between TRPC3 and RyR1 regulates the expressions of key triadic proteins. The Journal of biological chemistry 79 16484216
2015 TRPC3 contributes to regulation of cardiac contractility and arrhythmogenesis by dynamic interaction with NCX1. Cardiovascular research 74 25631581
2016 TRPC3-GEF-H1 axis mediates pressure overload-induced cardiac fibrosis. Scientific reports 71 27991560
2010 Transient receptor potential canonical 3 (TRPC3) mediates thrombin-induced astrocyte activation and upregulates its own expression in cortical astrocytes. The Journal of neuroscience : the official journal of the Society for Neuroscience 71 20881130
2007 TrpC3/C7 and Slo2.1 are molecular targets for metabotropic glutamate receptor signaling in rat striatal cholinergic interneurons. The Journal of neuroscience : the official journal of the Society for Neuroscience 65 17699666
2015 Brain-derived neurotrophic factor regulates TRPC3/6 channels and protects against myocardial infarction in rodents. International journal of biological sciences 64 25892961
2009 Inhibition of TRPC1/TRPC3 by PKG contributes to NO-mediated vasorelaxation. American journal of physiology. Heart and circulatory physiology 64 19502552
2005 Increased transient receptor potential channel TRPC3 expression in spontaneously hypertensive rats. American journal of hypertension 62 16280289
2018 LncRNA SNHG5 promotes growth and invasion in melanoma by regulating the miR-26a-5p/TRPC3 pathway. OncoTargets and therapy 61 30636880
2022 TRPC3 shapes the ER-mitochondria Ca2+ transfer characterizing tumour-promoting senescence. Nature communications 59 35177596
2017 TRPC3-Nox2 complex mediates doxorubicin-induced myocardial atrophy. JCI insight 59 28768915
2010 Ca2+ influx and protein scaffolding via TRPC3 sustain PKCbeta and ERK activation in B cells. Journal of cell science 59 20179100
2008 TRPC3-interacting triadic proteins in skeletal muscle. The Biochemical journal 57 18215135
2014 TRPC3 channels critically regulate hippocampal excitability and contextual fear memory. Behavioural brain research 55 25513972
2017 Role of TRPC3 and TRPC6 channels in the myocardial response to stretch: Linking physiology and pathophysiology. Progress in biophysics and molecular biology 53 28645743
2019 TRPC3 Regulates the Proliferation and Apoptosis Resistance of Triple Negative Breast Cancer Cells through the TRPC3/RASA4/MAPK Pathway. Cancers 52 31003514
2018 TRPC3 as a Target of Novel Therapeutic Interventions. Cells 51 30037143
2014 Contribution of TRPC3 to store-operated calcium entry and inflammatory transductions in primary nociceptors. Molecular pain 51 24965271
2006 Calcium store contents control the expression of TRPC1, TRPC3 and TRPV6 proteins in LNCaP prostate cancer cell line. Cell calcium 51 16529812
2019 TRPC3 is a major contributor to functional heterogeneity of cerebellar Purkinje cells. eLife 50 31486767
2011 mGluR1/TRPC3-mediated Synaptic Transmission and Calcium Signaling in Mammalian Central Neurons. Cold Spring Harbor perspectives in biology 49 21441586
2018 miR-26a inhibits atherosclerosis progression by targeting TRPC3. Cell & bioscience 48 29387339
2013 TRPC3 regulates release of brain-derived neurotrophic factor from human airway smooth muscle. Biochimica et biophysica acta 48 23899746
2009 Enhanced expression of STIM1/Orai1 and TRPC3 in platelets from patients with type 2 diabetes mellitus. Blood cells, molecules & diseases 43 19447651
2011 TRPC3 channel contributes to nitric oxide release: significance during normoxia and hypoxia-reoxygenation. Cardiovascular research 42 21493700
2008 TRPC3 controls agonist-stimulated intracellular Ca2+ release by mediating the interaction between inositol 1,4,5-trisphosphate receptor and RACK1. The Journal of biological chemistry 42 18755685
2008 Involvement of native TRPC3 proteins in ATP-dependent expression of VCAM-1 and monocyte adherence in coronary artery endothelial cells. Arteriosclerosis, thrombosis, and vascular biology 42 18787184
2006 Protein kinase C can inhibit TRPC3 channels indirectly via stimulating protein kinase G. Journal of cellular physiology 42 16331690
2015 Proarrhythmic effect of sustained EPAC activation on TRPC3/4 in rat ventricular cardiomyocytes. Journal of molecular and cellular cardiology 40 26219954
2014 Calcium sensing receptor modulates extracellular calcium entry and proliferation via TRPC3/6 channels in cultured human mesangial cells. PloS one 40 24905090
2012 Different binding property of STIM1 and its novel splice variant STIM1L to Orai1, TRPC3, and TRPC6 channels. Biochemical and biophysical research communications 40 23068106
2019 Trimetazidine prevents diabetic cardiomyopathy by inhibiting Nox2/TRPC3-induced oxidative stress. Journal of pharmacological sciences 39 30962089
2008 TRPC3 is the erythropoietin-regulated calcium channel in human erythroid cells. The Journal of biological chemistry 38 18276585
2017 TRPC3 Channels in Cardiac Fibrosis. Frontiers in cardiovascular medicine 37 28936433
2012 Role of TRPC1 and TRPC3 channels in contraction and relaxation of mouse thoracic aorta. Journal of vascular research 37 23095462
2014 Activation of calcium-sensing receptor increases TRPC3/6 expression in T lymphocyte in sepsis. Molecular immunology 35 25467798
2022 PLAA suppresses ovarian cancer metastasis via METTL3-mediated m6A modification of TRPC3 mRNA. Oncogene 33 35869392
2014 The Moonwalker mouse: new insights into TRPC3 function, cerebellar development, and ataxia. Cerebellum (London, England) 33 24797279
2017 TRPC6 counteracts TRPC3-Nox2 protein complex leading to attenuation of hyperglycemia-induced heart failure in mice. Scientific reports 32 28790356
2011 Impairment of survival signaling and efferocytosis in TRPC3-deficient macrophages. Biochemical and biophysical research communications 32 21684255
2011 Upregulated TRPC3 and Downregulated TRPC1 Channel Expression during Hypertension is Associated with Increased Vascular Contractility in Rat. Frontiers in physiology 32 21811471
2004 TRPC3-like protein and vitamin D receptor mediate 1alpha,25(OH)2D3-induced SOC influx in muscle cells. The international journal of biochemistry & cell biology 32 15203106
2017 Treatment with TREK1 and TRPC3/6 ion channel inhibitors upregulates microRNA expression in a mouse model of chronic mild stress. Neuroscience letters 31 28716528
2021 Progesterone receptor isoform B regulates the Oxtr-Plcl2-Trpc3 pathway to suppress uterine contractility. Proceedings of the National Academy of Sciences of the United States of America 30 33707208
2021 TRPC3 promotes tumorigenesis of gastric cancer via the CNB2/GSK3β/NFATc2 signaling pathway. Cancer letters 30 34311033
2019 Protective mechanism of SIRT1 on Hcy-induced atrial fibrosis mediated by TRPC3. Journal of cellular and molecular medicine 30 31680473
2015 The contribution of TRPC1, TRPC3, TRPC5 and TRPC6 to touch and hearing. Neuroscience letters 29 26520460
2014 Reduced endoplasmic reticulum stress-induced apoptosis and impaired unfolded protein response in TRPC3-deficient M1 macrophages. American journal of physiology. Cell physiology 29 25031020
2022 TRPC3 channel gating by lipids requires localization at the ER/PM junctions defined by STIM1. The Journal of cell biology 28 35416932
2019 Ibudilast attenuates doxorubicin-induced cytotoxicity by suppressing formation of TRPC3 channel and NADPH oxidase 2 protein complexes. British journal of pharmacology 28 31241172
2018 Transient Receptor Potential Channels TRPM4 and TRPC3 Critically Contribute to Respiratory Motor Pattern Formation but not Rhythmogenesis in Rodent Brainstem Circuits. eNeuro 28 29435486
2016 Transient Receptor Potential Canonical 3 (TRPC3) Channels Are Required for Hypothalamic Glucose Detection and Energy Homeostasis. Diabetes 28 27899482
2014 Upregulation and Diverse Roles of TRPC3 and TRPC6 in Synaptic Reorganization of the Mossy Fiber Pathway in Temporal Lobe Epilepsy. Molecular neurobiology 28 25213992
2015 The mutant Moonwalker TRPC3 channel links calcium signaling to lipid metabolism in the developing cerebellum. Human molecular genetics 27 25908616
2019 TRPC3-Nox2 axis mediates nutritional deficiency-induced cardiomyocyte atrophy. Scientific reports 26 31278358
2019 TRPC3 deficiency attenuates high salt-induced cardiac hypertrophy by alleviating cardiac mitochondrial dysfunction. Biochemical and biophysical research communications 26 31543348
2017 TRPC1- and TRPC3-dependent Ca2+ signaling in mouse cortical astrocytes affects injury-evoked astrogliosis in vivo. Glia 26 28636132
2011 The transient receptor potential (TRP) channel TRPC3 TRP domain and AMP-activated protein kinase binding site are required for TRPC3 activation by erythropoietin. The Journal of biological chemistry 26 21757714
2021 TRPC3 and NALCN channels drive pacemaking in substantia nigra dopaminergic neurons. eLife 25 34409942
2014 TRPC3: a multifunctional signaling molecule. Handbook of experimental pharmacology 25 24756703
2014 Adaptive responses of TRPC1 and TRPC3 during skeletal muscle atrophy and regrowth. Muscle & nerve 24 23852583
2007 TRPC3: a multifunctional, pore-forming signalling molecule. Handbook of experimental pharmacology 24 17217051
2013 Chronic oxidative stress modulates TRPC3 and TRPM2 channel expression and function in rat primary cortical neurons: relevance to the pathophysiology of bipolar disorder. Brain research 23 23602965
2008 TRPC3 activation by erythropoietin is modulated by TRPC6. The Journal of biological chemistry 23 19074769
2022 Inhibition of TRPC3 channels by a novel pyrazole compound confers antiseizure effects. Epilepsia 22 35179226
2015 TRPC3 regulates the automaticity of embryonic stem cell-derived cardiomyocytes. International journal of cardiology 22 26512833
2010 TRPC3 cation channel plays an important role in proliferation and differentiation of skeletal muscle myoblasts. Experimental & molecular medicine 22 20644344
2015 The involvement of TRPC3 channels in sinoatrial arrhythmias. Frontiers in physiology 21 25859221
2015 TRPC3-dependent synaptic transmission in central mammalian neurons. Journal of molecular medicine (Berlin, Germany) 21 26041382
2009 TRPC3 ion channel subunit immunolocalization in the cochlea. Histochemistry and cell biology 21 19882163
2017 TRPC3- and ETB receptor-mediated PI3K/AKT activation induces vasogenic edema formation following status epilepticus. Brain research 20 28764936
2015 Nicotine Induces Cardiomyocyte Hypertrophy Through TRPC3-Mediated Ca2+/NFAT Signalling Pathway. The Canadian journal of cardiology 19 26952156
2011 Candidate screening of the TRPC3 gene in cerebellar ataxia. Cerebellum (London, England) 19 21321808
2010 Developmental regulation of TRPC3 ion channel expression in the mouse cochlea. Histochemistry and cell biology 19 20229053
2011 Expression and association of TRPC1 with TRPC3 during skeletal myogenesis. Muscle & nerve 18 21996795
2008 Autoantibodies against TRPC3 and ryanodine receptor in myasthenia gravis. Journal of neuroimmunology 18 18602703

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