Affinage

TRPC6

Short transient receptor potential channel 6 · UniProt Q9Y210

Length
931 aa
Mass
106.3 kDa
Annotated
2026-06-10
100 papers in source corpus 37 papers cited in narrative 37 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

TRPC6 is a receptor-operated, diacylglycerol (DAG)-activated non-selective cation channel that converts Gq-coupled receptor/PLC signaling into Ca2+ entry to control cytoskeletal dynamics, cell differentiation, and survival across podocytes, fibroblasts, neurons, and cardiomyocytes (PMID:11278449, PMID:15023993, PMID:23022034). It assembles as a homotetramer with a two-layer architecture in which an N-terminal ankyrin/C-terminal coiled-coil cytosolic bell holds the transmembrane channel layer, and small-molecule agonists and antagonists act at distinct interfacial and S1-S4/TRP-helix pockets that govern gating (PMID:29700422, PMID:32149605). Activation is DAG-dependent and store-independent: muscarinic Gq stimulation and exogenous OAG open the channel cooperatively while store depletion does not, and PKC provides negative feedback (PMID:11278449, PMID:15023993). Channel function is positively tuned by H2O2-mediated cysteine oxidation, which also promotes surface translocation (PMID:20501650), by Fyn phosphorylation (PMID:21220918), and by WNK1 acting through PI4KIIIα to drive Gαq/PLC-β signaling (PMID:31022353), while STIM1 redistributes TRPC6 to the ER (PMID:25088676) and synaptopodin and an intact actin/microtubule cytoskeleton limit its surface abundance and gating (PMID:27020855, PMID:33922367). Biogenesis and surface expression require N-glycosylation and ER insertase machinery including the EMC and TMEM208/WDR83OS pathway (PMID:31266804). Downstream, TRPC6 Ca2+ entry engages calcineurin/NFAT to drive myofibroblast transdifferentiation and fibrosis (PMID:23022034, PMID:27932059), complexes with RhoA to restrain migration via actin remodeling (PMID:20978238), and activates CaMKIV/CREB to promote neuronal dendritic growth and survival (PMID:18559891). In disease, TRPC6 Ca2+ signaling drives podocyte injury through NOX4-derived H2O2 (PMID:29793963) and calpain-mediated autophagy impairment (PMID:37678257), contributes to angiotensin II-dependent albuminuria (PMID:21258036), and gain-of-function or dominant-negative loss-of-function missense mutations that disrupt subunit-interface interactions cause familial FSGS (PMID:32149605, PMID:26892346).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2001 High

    Established TRPC6 as a receptor-operated, DAG-sensitive channel rather than a store-operated one, defining its core activation logic and the structural elements required for activation and biogenesis.

    Evidence Transfection of rat TRPC6 in COS cells with Ca2+/Ba2+ influx, truncation mutants, and glycosylation analysis

    PMID:11278449

    Open questions at the time
    • Did not resolve how DAG engages the channel structurally
    • Glycosylation requirement defined a segment but not the molecular machinery
  2. 2004 High

    Refined the activation model by showing cooperative DAG gating, PKC-mediated negative feedback, and receptor inputs beyond DAG generation, indicating multi-tiered control of channel opening.

    Evidence Whole-cell patch-clamp and FLIPR in TRPC6-expressing HEK cells with pharmacological dissection

    PMID:15023993

    Open questions at the time
    • Identity of the additional receptor-derived signal not defined
    • PKC phosphorylation sites not mapped
  3. 2008 High

    Connected TRPC6 Ca2+ entry to a defined transcriptional output (CaMKIV/CREB) controlling neuronal dendritic growth, establishing a survival/growth signaling axis.

    Evidence Neuronal overexpression/shRNA, dominant-negative CaMKIV/CREB, transgenic mice

    PMID:18559891

    Open questions at the time
    • Did not address endogenous receptor that activates TRPC6 in neurons
    • Link to disease neurobiology not tested
  4. 2010 High

    Identified two distinct post-translational/protein-interaction control nodes: H2O2/thiol oxidation that enhances activity and surface delivery, and a TRPC6-RhoA complex that couples Ca2+ entry to cytoskeletal contraction and migration restraint.

    Evidence Electrophysiology, surface biotinylation, thiol pharmacology; reciprocal Co-IP with migration assays

    PMID:20501650 PMID:20978238

    Open questions at the time
    • Oxidized cysteine residues not pinpointed
    • Mechanism by which RhoA binding alters channel or downstream actin not resolved
  5. 2012 High

    Demonstrated that TRPC6 is necessary and sufficient for TGF-β/angiotensin II-induced myofibroblast transdifferentiation via a calcineurin-dependent program, linking the channel to tissue fibrosis.

    Evidence Genome-wide screen, Trpc6-/- fibroblasts, promoter assay, in vivo wound-healing models with calcineurin inhibition

    PMID:23022034

    Open questions at the time
    • NFAT target genes driving differentiation not enumerated
    • Did not separate channel activity from scaffolding roles
  6. 2011 High

    Placed TRPC6 in podocyte injury pathways, showing it mediates angiotensin II-dependent Ca2+ entry and albuminuria and is upregulated and phosphorylated by Fyn downstream of TGF-β1/Smad3-ERK-NF-κB.

    Evidence Trpc6-/- mice with angiotensin II infusion and podocyte patch-clamp; Co-IP and knockdown of Fyn

    PMID:21220918 PMID:21258036

    Open questions at the time
    • Fyn phosphosites on TRPC6 not mapped
    • Relative contribution of expression vs gating in vivo unresolved
  7. 2014 Medium

    Defined regulators of TRPC6 localization and physiology: STIM1 drives ER redistribution reducing heteromultimerization, TRPC3/TRPC6 act redundantly in cardiac hypertrophy, and TRPC6 sets resting membrane potential in stromal cells linked to cell cycle.

    Evidence Co-IP/fractionation; TRPC3/TRPC6 double-KO pressure-overload mice; siRNA with cell-cycle and SOCE analysis

    PMID:24453217 PMID:25041367 PMID:25088676

    Open questions at the time
    • STIM1-TRPC6 redistribution mechanism single lab
    • Functional redundancy with TRPC3 limits attribution to TRPC6 alone
  8. 2016 Medium

    Resolved trafficking control and disease genetics: synaptopodin and the actin/microtubule cytoskeleton limit surface TRPC6, insulin upregulates TRPC6 via calcineurin/NFAT, and FSGS mutations include dominant-negative loss-of-function at the subunit interface.

    Evidence Bidirectional manipulation with biotinylation and in vivo proteinuria; calcineurin/NFAT inhibitors; electrophysiology of 19 mutants with dominant-negative co-expression and modeling

    PMID:26849622 PMID:26892346 PMID:27020855

    Open questions at the time
    • Mechanism of synaptopodin-dependent internalization incompletely defined
    • Genotype-phenotype relationship across gain- vs loss-of-function mutations not fully reconciled
  9. 2018 High

    Provided structural and oxidative-pathway mechanisms: cryo-EM defined the antagonist (BTDM) binding mode, and NOX4-derived H2O2 was shown to drive TRPC6-dependent podocyte Ca2+ entry and damage in diabetic kidney disease.

    Evidence Single-particle cryo-EM at 3.8 Å; SSNox4-/- and Trpc6-/- mice with glomerular Ca2+ imaging and electron microscopy

    PMID:29700422 PMID:29793963

    Open questions at the time
    • First structure lacked agonist-bound state
    • How NOX4-H2O2 spatially couples to TRPC6 channels not resolved
  10. 2019 High

    Defined the biogenesis machinery and an upstream activating kinase: N-glycosylation plus EMC/TMEM208/WDR83OS insertase pathways are required for TRPC6 expression and surface delivery, and WNK1-PI4KIIIα stimulates TRPC6 via Gαq/PLC-β.

    Evidence Genome-wide CRISPR screen with glycosylation-site mutagenesis and biotinylation; patch-clamp with WNK1 and calcineurin inhibition

    PMID:31022353 PMID:31266804

    Open questions at the time
    • Order of glycosylation, insertase action, and folding steps not fully sequenced
    • Direct vs indirect WNK1 action on PI4KIIIα not separated
  11. 2023 High

    Extended TRPC6 Ca2+ signaling to autophagy and splicing control: calpain activation downstream of TRPC6 impairs podocyte autophagy in diabetes, and TRPC6 Ca2+ entry represses ESRP1 to reprogram integrin α6 splicing in breast cancer.

    Evidence TRPC6 knockdown with diabetic mouse models and calpastatin rescue; gain/loss-of-function with splicing reporters and TAZ/Myc readouts in TNBC

    PMID:37678257 PMID:37910503

    Open questions at the time
    • Calpain substrates mediating autophagy block not identified
    • How Ca2+ represses ESRP1 mechanistically unresolved
  12. 2024 Medium

    Linked TRPC6 to cardiomyocyte death by showing it drives CaMKII activation, mPTP opening, and necroptosis in ischemia/reperfusion injury.

    Evidence Trpc6-/- mouse I/R and H9c2 H/R models with Ca2+ imaging, CaMKII phosphorylation, mPTP and ROS assays

    PMID:39134250

    Open questions at the time
    • Single lab
    • Direct coupling of TRPC6 Ca2+ to CaMKII compartmentalization not shown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the distinct ligand-binding pockets, oxidative/phosphorylation inputs, and cytoskeletal/trafficking regulators are integrated to set TRPC6 activity in a cell-type-specific manner — and whether gain- versus loss-of-function disease mutations converge on a single channel parameter — remains unresolved.
  • No unified gating model integrating DAG, H2O2, phosphorylation, and mechanical inputs
  • Mechanosensitivity of TRPC6 alone is inconsistent across heterologous systems
  • Endogenous receptor-to-channel signaling cascades differ by tissue

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 4 GO:0005198 structural molecule activity 2 GO:0008289 lipid binding 2 GO:0140299 molecular sensor activity 2
Localization
GO:0005886 plasma membrane 4 GO:0005783 endoplasmic reticulum 2
Pathway
R-HSA-1643685 Disease 6 R-HSA-162582 Signal Transduction 4 R-HSA-5357801 Programmed Cell Death 3
Partners
CYBBFYNNCX1RHOASTIM1TMEM208TRPC3WDR83OS

Evidence

Reading pass · 37 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2018 Cryo-EM structure of human TRPC6 homotetramer at 3.8 Å resolution reveals a two-layer architecture with a bell-shaped cytosolic layer (containing N-terminal ankyrin repeats and C-terminal coiled-coil) holding the transmembrane layer; extensive inter-subunit interactions of cytosolic domains contribute to tetramer assembly. The high-affinity inhibitor BTDM wedges between the S5-S6 pore domain and voltage sensor-like domain to inhibit channel opening. Single-particle cryo-electron microscopy Cell research High 29700422
2020 Cryo-EM structures of TRPC6 in antagonist-bound and agonist-bound states reveal two novel small-molecule recognition sites: the antagonist binds a cytoplasm-facing pocket formed by S1-S4 and the TRP helix, whereas the agonist wedges at the subunit interface between S6 and the pore helix. Mutagenesis confirmed these binding sites. Disease-related gain-of-function mutations disrupt interfacial interactions, as shown by structural and mutagenesis analyses. Cryo-EM structure determination combined with site-directed mutagenesis eLife High 32149605
2001 Rat TRPC6 (rTRP6) is activated by diacylglycerol (OAG) and by Gq-coupled M5 muscarinic acetylcholine receptor stimulation but not by passive depletion of intracellular Ca2+ stores (thapsigargin), establishing it as a receptor-operated, DAG-sensitive channel. The N-terminal 3–56 amino acids are required for OAG-induced activation, and the 735–802 segment (downstream of TM6) is required for protein processing/glycosylation. The truncated isoform rTRP6C, which lacks residues 735–802, is not glycosylated and shows no Ca2+ or Ba2+ influx. Transient transfection of COS cells; Ca2+/Ba2+ influx assays; antisense and dominant-negative constructs; glycosylation analysis The Journal of biological chemistry High 11278449
2004 Human TRPC6 expressed in HEK cells is activated by muscarinic receptor stimulation (carbachol) and by exogenous DAG (OAG) with a cooperative concentration-response relationship (Hill coefficient 3–4). Thapsigargin, ionomycin, and IP3 dialysis do not activate TRPC6. PKC activator PMA blocks the CCh response >90% but does not acutely affect TRPC6 alone, suggesting PKC-mediated negative feedback. Sub-threshold concentrations of CCh and OAG act synergistically, indicating that receptor-mediated events beyond DAG generation contribute to channel activation. Whole-cell patch-clamp and fluorescence-based FLIPR assay in TRPC6-expressing HEK cells The Journal of biological chemistry High 15023993
2010 TRPC6 forms a molecular complex with RhoA in fibroblasts and podocytes. TRPC6-mediated Ca2+ influx increases RhoA activity, thereby inhibiting cell migration. Antagonistically, TRPC5 is in complex with Rac1 and promotes cell migration via Rac1 activation. These two channels act as opposing regulators of actin dynamics and cell motility. Co-immunoprecipitation to identify TRPC6-RhoA and TRPC5-Rac1 complexes; Ca2+ imaging; migration assays; siRNA knockdown Science signaling High 20978238
2012 TRPC6 is necessary and sufficient for TGF-β- and angiotensin II-induced myofibroblast transdifferentiation. TGF-β and angiotensin II induce TRPC6 expression via p38 MAPK–SRF signaling acting on the TRPC6 promoter. Once induced, TRPC6 activates the Ca2+-responsive phosphatase calcineurin, which drives myofibroblast differentiation. Calcineurin inhibition prevents TRPC6-dependent transdifferentiation and dermal wound healing in vivo. Genome-wide screen; TRPC6 overexpression and Trpc6-/- fibroblasts; in vivo dermal and cardiac wound-healing models; TRPC6 promoter assay; pharmacological calcineurin inhibition Developmental cell High 23022034
2010 H2O2 activates TRPC6 channels via modification of intracellular thiol groups (cysteine oxidation): N-ethylmaleimide and thimerosal (thiol-modifying agents) mimic the H2O2 effect, while dithiothreitol and glutathione antagonize it. H2O2 also promotes TRPC6 translocation to the cell surface (biotinylation and confocal imaging) and sensitizes channels to DAG. The effect is seen in cell-attached but not inside-out patches, indicating requirement for an intracellular signal. Ca2+ entry assays; electrophysiology (cell-attached and inside-out patches); biotinylation surface expression assay; confocal imaging of TRPC6-EGFP; pharmacological thiol manipulation The Journal of biological chemistry High 20501650
2008 TRPC6 promotes hippocampal neuron dendritic growth via the CaMKIV-CREB pathway. TRPC6 overexpression increases CaMKIV and CREB phosphorylation and promotes dendritic growth; shRNA-mediated TRPC6 knockdown suppresses both. Dominant-negative CaMKIV or CREB blocks TRPC6-induced dendritic growth. Inhibition of Ca2+ influx abolishes the TRPC6 effect. TRPC6 transgenic mice show enhanced CaMKIV/CREB phosphorylation and increased dendritic growth. Neuronal overexpression and shRNA knockdown; phosphorylation assays; dominant-negative constructs; Ca2+ influx inhibition; transgenic mice Journal of cell science High 18559891
2009 Hypoxia-induced Notch1 activation drives TRPC6 expression in glioblastoma cells. TRPC6 causes sustained intracellular Ca2+ elevation coupled to calcineurin-NFAT pathway activation, promoting tumor growth, invasion, and angiogenesis. TRPC6 knockdown inhibits these malignant phenotypes; pharmacological inhibition of calcineurin-NFAT substantially reduces them. siRNA knockdown of TRPC6 in GBM cell lines and in vivo xenograft; Ca2+ imaging; calcineurin-NFAT pathway inhibitor treatment Cancer research Medium 20028870
2011 TRPC6 mediates angiotensin II-dependent increases in podocyte membrane current and Ca2+ entry. TRPC6-deficient mice develop less albuminuria during angiotensin II infusion despite similar hypertension. Whole-cell patch-clamp recordings show that angiotensin II and a direct TRPC6 activator augment membrane currents in wild-type but not TRPC6-deficient podocytes. TRPC6-/- mouse model; angiotensin II infusion protocol; whole-cell patch-clamp of primary cultured podocytes Journal of the American Society of Nephrology : JASN High 21258036
2011 TGF-β1 upregulates TRPC6 protein expression in podocytes via the Smad3-ERK-NF-κB pathway, and Fyn kinase phosphorylates TRPC6 to activate channel function. Immunoprecipitation shows Fyn interacts with TRPC6 in podocytes. Fyn knockdown blocks TRPC6 phosphorylation and intracellular Ca2+ elevation without affecting TRPC6 protein levels. ERK and NF-κB inhibitors suppress both TRPC6 upregulation and Ca2+ flux. Co-immunoprecipitation; siRNA knockdown of Fyn and TRPC6; Western blot for phospho-TRPC6; kinase inhibitors; intracellular Ca2+ measurement Cellular physiology and biochemistry Medium 21220918
2018 NOX4-derived H2O2 activates TRPC6-dependent Ca2+ influx in podocytes, contributing to podocyte damage in diabetic kidney disease. H2O2 stimulates TRPC-dependent calcium influx in wild-type podocytes but this is blunted in Trpc6-knockout and Trpc5/6 double-knockout mice; electron microscopy shows equal protection from H2O2-induced damage in both knockouts. SSNox4-/- and Trpc6-/- mouse models; live calcium imaging in freshly isolated glomeruli; electrophysiology; electron microscopy; streptozotocin-induced diabetes Journal of the American Society of Nephrology : JASN High 29793963
2014 STIM1 regulates TRPC6 subcellular localization: STIM1 overexpression attenuates TRPC6 plasma membrane expression and promotes its translocation to the endoplasmic reticulum. This redistribution reduces TRPC6 heteromultimerization with TRPC1 and TRPC3. TRPC6 expression in the ER increases passive Ca2+ efflux and basal cytosolic Ca2+ but not ER Ca2+ accumulation. Co-immunoprecipitation; subcellular fractionation; fluorescence imaging; Ca2+ flux measurements The Biochemical journal Medium 25088676
2019 N-linked glycosylation of TRPC6 at two N-glycosylation sites is required for normal surface expression and channel activity: mutating both N-glycosylation sites reduces surface expression of gain-of-function TRPC6 and abrogates cytotoxicity in podocytes. The ER membrane protein complex (EMC) transmembrane insertase and TMEM208 (part of a SND ER-targeting pathway), together with WDR83OS (which interacts with both TRPC6 and TMEM208), are required for TRPC6 protein expression. Genome-wide CRISPR/Cas screen; site-directed mutagenesis of N-glycosylation sites; surface biotinylation; Ca2+ influx assays; MGAT1 knockout The Journal of biological chemistry High 31266804
2016 Synaptopodin limits TRPC6 surface expression in podocytes via an actin- and microtubule-dependent mechanism. Synaptopodin knockdown increases TRPC6 plasma membrane abundance and TRPC6-mediated Ca2+ influx, leading to apoptosis; synaptopodin overexpression decreases it. In vivo, synaptopodin knockdown increases podocyte surface TRPC6, and cyclosporin A (which stabilizes synaptopodin) reverses LPS-induced increase in surface TRPC6. The protective effect of cyclosporin A on LPS-induced proteinuria is attenuated in TRPC6 KO mice. siRNA knockdown and overexpression in cultured podocytes; surface biotinylation; Ca2+ influx; apoptosis assay; in vivo mouse proteinuria model; TRPC6 KO mice Journal of the American Society of Nephrology : JASN High 27020855
2016 TRPC6 G757D is a loss-of-function mutation located in the TRPC6-TRPC6 interface domain; 3D modeling predicts steric hindrance disrupting the channel complex, and functional characterization confirms loss-of-function. When co-expressed with wild-type TRPC6 (mimicking patient heterozygosity), G757D exerts a dominant-negative effect. Five TRPC6 FSGS mutations (N125S, L395A, G757D, L780P, R895L) cause loss-of-function, establishing loss of TRPC6 function as an additional mechanism for hereditary FSGS. In silico structural modeling; functional electrophysiology of 19 TRPC6 mutations in heterologous expression; co-expression dominant-negative assays Journal of the American Society of Nephrology : JASN Medium 26892346
2012 TRPC6 inhibits NMDA receptor-mediated Ca2+ overload and protects neurons from ischemic excitotoxicity. Overexpressing TRPC6 suppresses NMDA-induced Ca2+ elevation and neuronal death; TRPC6 knockdown aggravates Ca2+ overload under excitotoxicity. TRPC6 transgenic mice show smaller infarct volumes and better behavioral outcomes after cerebral ischemia. Neuronal overexpression and knockdown; Ca2+ imaging with NMDA challenge; OGD model; TRPC6 transgenic mice with MCAO model Journal of neurochemistry Medium 23043486
2017 TRPC6 regulates mitochondrial dynamics in dentate granule cells by activating ERK1/2, which phosphorylates DRP1-S616 to promote mitochondrial fission. TRPC6 knockdown decreases ERK1/2 phosphorylation and DRP1-S616 phosphorylation, causing mitochondrial elongation and exacerbating status epilepticus-induced neurodegeneration. ERK1/2 inhibition phenocopies TRPC6 knockdown. In vivo TRPC6 siRNA knockdown in rat hippocampus; status epilepticus model; Western blot for ERK1/2 and DRP1 phosphorylation; mitochondrial morphology analysis Neuropharmacology Medium 28479396
2016 TRPC6 channel activation in glomerular mesangial cells stimulates calcineurin/NFAT signaling and increases FasL expression, activating caspase-8 and triggering apoptosis via the FasL/Fas pathway. These effects are blocked by intracellular Ca2+ chelation (BAPTA), calcineurin/NFAT inhibitor VIVIT, Fas-blocking antibody, and TRPC6 knockdown. Hyperforin-induced TRPC6 activation; TRPC6 siRNA knockdown; NFATc1 nuclear translocation assay; caspase-8 activity; Fas-blocking antibody; Ca2+ imaging Scientific reports Medium 27383564
2018 TGF-β induces formation of a TRPC6/NCX1 molecular complex in hepatocellular carcinoma cells; this complex mediates TGF-β-stimulated intracellular Ca2+ increases and regulates cell migration, invasion, and intrahepatic metastasis. There is positive feedback between TRPC6/NCX1 Ca2+ signaling and Smad signaling. Co-immunoprecipitation demonstrating TRPC6/NCX1 complex; Ca2+ imaging; migration and invasion assays; in vivo intrahepatic metastasis in nude mice Cancer research Medium 29500176
2017 TRPC6 counteracts the TRPC3-Nox2 protein complex: TRPC6 can interact with Nox2, but TRPC6 abundance is inversely correlated with Nox2 abundance, suggesting TRPC6 destabilizes the TRPC3-Nox2 complex. TRPC6 deletion in hyperglycemic mice exacerbates cardiac contractility reduction and oxidative stress, consistent with a role for TRPC6 in attenuating TRPC3-Nox2-mediated ROS production. Co-immunoprecipitation of TRPC6-Nox2; TRPC6-/- and TRPC3-/- mouse models; streptozotocin-induced hyperglycemia; cardiac contractility and lipid peroxide measurements Scientific reports Medium 28790356
2017 LPS activates TRPC6 expression and Ca2+ entry in bronchial epithelial cells via TLR4/PI3K/Akt signaling. TRPC6-dependent Ca2+ influx is required for activation of ERK1/2, p38, and NF-κB pathways and subsequent IL-8 and IL-6 production. TRPC6 knockdown reduces LPS-induced cytokine release. siRNA knockdown of TRPC6; pharmacological TRPC6 activation (Hyp9); Ca2+ imaging; Western blot for pathway activation; ELISA for cytokines American journal of physiology. Cell physiology Medium 29141922
2019 WNK1 promotes TRPC6-mediated Ca2+ influx and current by stimulating PI4KIIIα (phosphatidylinositol 4-kinase IIIα), which activates Gαq-coupled receptor/PLC-β signaling upstream of TRPC6. Inhibition of WNK1-mediated TRPC6 activation and downstream calcineurin attenuates NFATc1 activation and migration/proliferation of clear-cell renal cell carcinoma cells. Whole-cell patch-clamp for TRPC6 currents; Ca2+ imaging; WNK1 inhibition; calcineurin inhibitor; NFATc1 reporter assay; cell migration and proliferation assays FASEB journal Medium 31022353
2023 TRPC6-mediated Ca2+ entry in podocytes activates calpain, which impairs autophagy, causing podocyte injury in diabetic kidney disease. TRPC6 knockdown in podocytes increases autophagic flux by reducing calpain activity. Transgenic overexpression of the endogenous calpain inhibitor calpastatin, or pharmacological calpain inhibition, normalizes podocyte autophagic flux and reduces nephrin loss and albuminuria in diabetic mice. TRPC6 siRNA knockdown; diabetic mouse models (STZ/unilateral nephrectomy and BTBR ob/ob); transgenic calpastatin overexpression; calpain inhibitor treatment; autophagic flux assays Journal of the American Society of Nephrology : JASN High 37678257
2016 TRPC6 supports TGF-β1-induced myofibroblast differentiation in pulmonary fibrosis: TGF-β1 induces TRPC6 upregulation, increased Ca2+ influx, and nuclear NFAT localization in murine lung fibroblasts. TRPC6-deficient fibroblasts show reduced stress fiber formation, slower contraction rates, and less collagen production. TRPC6-/- mice are partially protected from bleomycin-induced pulmonary fibrosis. TRPC6-/- mouse bleomycin fibrosis model; Ca2+ imaging; NFAT nuclear translocation assay; stress fiber and contraction assays in primary lung fibroblasts Biochimica et biophysica acta. Molecular basis of disease Medium 27932059
2014 Combined genetic deletion of TRPC3 and TRPC6 (but not deletion of either alone) protects mice against pressure overload-induced cardiac hypertrophy and dysfunction, demonstrating functional redundancy between these channels in pathological cardiac hypertrophy. Single and double TRPC3/TRPC6 knockout mice subjected to pressure overload (transverse aortic constriction); echocardiography; histology Proceedings of the National Academy of Sciences of the United States of America Medium 24453217
2021 TRPC6 and Piezo1 both contribute to membrane stretch-mediated cation currents and Ca2+ influx in human pulmonary arterial endothelial cells. Only TRPC6 (not Piezo1) is sensitive to the DAG analog OAG. Hypo-osmotic membrane stretch enhances currents in TRPC6-transfected HEK cells, indicating TRPC6 has mechanosensitive properties in addition to DAG sensitivity. Whole-cell patch-clamp; Ca2+ imaging; TRPC6-selective blocker BI-749327; GsMTx4 (Piezo1 blocker); TRPC6-transfected HEK cells; OAG stimulation American journal of physiology. Cell physiology Medium 35968892
2014 TRPC6 controls resting membrane potential in bone marrow stromal cells: TRPC6 expression is highest in the G1 phase (least negative RMP) and lowest in S phase (most negative RMP). siRNA knockdown of TRPC6 causes hyperpolarization, increased store-operated Ca2+ entry (SOCE), and cell cycle redistribution toward S and G2/M phases with accumulation of cyclins A2 and B1. siRNA knockdown; cell cycle synchronization; patch-clamp membrane potential recording; flow cytometry; SOCE measurement British journal of pharmacology Medium 25041367
2021 Actin cytoskeleton disruption by cytochalasin D increases TRPC6 channel activity in CHO cells overexpressing TRPC6 and in native podocytes from freshly isolated glomeruli. Co-expression of mutant α-actinin-4 K255E (which solidifies the actin network) with TRPC6 decreases TRPC6 channel activity, demonstrating bidirectional feedback between actin cytoskeleton structure and TRPC6 gating. Cell-attached patch-clamp; scanning ion-conductance microscopy; cytochalasin D treatment; α-actinin-4 K255E co-expression in CHO cells and freshly isolated glomerular podocytes International journal of molecular sciences Medium 33922367
2013 The vitamin D receptor directly binds to the TRPC6 promoter (shown by ChIP) and reduces TRPC6 promoter activity (luciferase reporter), down-regulating TRPC6 expression in podocytes. In 1,25-D3-deficient mice, TRPC6 expression is increased with foot process effacement and proteinuria; 1,25-D3 supplementation normalizes TRPC6 expression, podocyte morphology, and proteinuria. Chromatin immunoprecipitation (ChIP); TRPC6 luciferase promoter assay; adriamycin nephropathy rat model; 1,25-hydroxylase KO mice; VDR ligand treatment The American journal of pathology High 23385000
2022 Pharmacological inhibition of TRPC6 (BI 749327) or TRPC6 gene deletion prolongs survival 2- to 3-fold in mdx/utrn-/- Duchenne muscular dystrophy mice, improving skeletal and cardiac muscle and bone defects. Gene pathways reduced by BI 749327 most prominently regulate fat metabolism and TGF-β1 signaling. TRPC6 gene-deleted and BI 749327-treated HET and homozygous mdx/utrn-/- mice; echocardiography; histology; RNA-seq pathway analysis JCI insight Medium 36099033
2017 TRPC6 channel activation (by hyperforin) or agonist-induced Ca2+ influx activates ERK phosphorylation in endothelial cells. This leads to p47phox phosphorylation, NADPH oxidase activation, and ROS production, which promotes MLCK-mediated myosin light chain phosphorylation and TRPC5 externalization. Knockdown of ERK, NADPH oxidase, or MLCK prevents TRPC5 externalization. TRPC6-/- endothelial cells fail to activate ERK in response to lysoPC. siRNA knockdown of ERK, NADPH oxidase, MLCK; TRPC6-/- endothelial cells; phosphorylation assays; TRPC5 surface expression measurement American journal of physiology. Cell physiology Medium 28835433
2023 TRPC6-mediated Ca2+ entry represses ESRP1 (epithelial splicing regulatory protein 1), enabling expression of the integrin α6B splice variant. TRPC6 and α6B function together to activate TAZ and repress Myc, facilitating breast cancer stem cell properties and chemotherapy persistence. TRPC6 inhibition sensitizes TNBC cells to chemotherapy by reversing α6 integrin splicing and inducing Myc. TRPC6 gain- and loss-of-function; splicing reporter assays; ESRP1 expression analysis; TAZ and Myc pathway readouts; in vitro and in vivo TNBC chemotherapy models Cell reports Medium 37910503
2024 In myocardial ischemia/reperfusion injury, TRPC6 is upregulated and mediates Ca2+ entry that activates CaMKII phosphorylation, promoting mPTP opening, oxidative stress, and necroptosis. TRPC6 knockout reduces intracellular Ca2+, CaMKII phosphorylation, ROS, mPTP opening, and improves mitochondrial structure and cardiac function after I/R. TRPC6-/- mouse I/R model; H9c2 H/R cell model; Ca2+ imaging; CaMKII phosphorylation; mPTP opening assay; ROS measurement; echocardiography Cellular signalling Medium 39134250
2022 TRPC6 promotes zinc ion influx in renal tubular epithelial cells; this zinc influx upregulates intracellular A20, which inhibits NLRP3 inflammasome activation and attenuates pyroptosis. TRPC6 inhibition reduces zinc influx, increases NLRP3-driven pyroptosis, and worsens I/R renal injury; these effects are reversed by exogenous zinc chloride. TRPC6 inhibitor (SAR7334); zinc ion chelator (TPEN); zinc supplementation (ZnCl2); A20 knockdown/overexpression; NLRP3/caspase-1/IL-1β/IL-18 measurement; mouse I/R model FASEB journal Medium 36036542
2007 Overexpression of TRPC1 or TRPC6 in COS or CHO cells does not significantly alter the amplitude of mechanosensitive (stretch-activated) Ca2+-permeable cation channel currents as measured by fast pressure-clamp, indicating that neither channel alone constitutes a mechanosensitive current in these heterologous systems. Transient transfection of TRPC1 and TRPC6 in COS/CHO cells; fast pressure-clamp electrophysiology Pflugers Archiv : European journal of physiology Medium 17957383
2016 Insulin increases TRPC6 mRNA and protein expression in podocytes through activation of the calcineurin-NFAT pathway: tacrolimus, cyclosporin A, and an NFAT inhibitor all block insulin-induced TRPC6 upregulation and NFATc1 activation. Insulin-stimulated TRPC6 surface expression is accompanied by increased trans-plasma-membrane cation influx. qRT-PCR; immunoblotting; immunofluorescence; NFATc1 activity assay; Ca2+ influx (fluorescence spectrophotometry and Mn2+ quench); calcineurin/NFAT inhibitors Cellular physiology and biochemistry Medium 26849622

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 A TRPC6-dependent pathway for myofibroblast transdifferentiation and wound healing in vivo. Developmental cell 296 23022034
2003 PDGF stimulates pulmonary vascular smooth muscle cell proliferation by upregulating TRPC6 expression. American journal of physiology. Cell physiology 289 12529250
2010 Antagonistic regulation of actin dynamics and cell motility by TRPC5 and TRPC6 channels. Science signaling 224 20978238
2007 Revisiting TRPC1 and TRPC6 mechanosensitivity. Pflugers Archiv : European journal of physiology 219 17957383
2009 TRPC1 and TRPC6 channels cooperate with TRPV4 to mediate mechanical hyperalgesia and nociceptor sensitization. The Journal of neuroscience : the official journal of the Society for Neuroscience 172 19439599
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
2009 Receptor channel TRPC6 is a key mediator of Notch-driven glioblastoma growth and invasiveness. Cancer research 165 20028870
2018 Structure of the receptor-activated human TRPC6 and TRPC3 ion channels. Cell research 155 29700422
2008 TRPC6 channels promote dendritic growth via the CaMKIV-CREB pathway. Journal of cell science 142 18559891
2010 TRPC6 channels and their binding partners in podocytes: role in glomerular filtration and pathophysiology. American journal of physiology. Renal physiology 136 20685822
2018 A NOX4/TRPC6 Pathway in Podocyte Calcium Regulation and Renal Damage in Diabetic Kidney Disease. Journal of the American Society of Nephrology : JASN 117 29793963
2011 TRPC6 enhances angiotensin II-induced albuminuria. Journal of the American Society of Nephrology : JASN 115 21258036
2011 Balancing calcium signals through TRPC5 and TRPC6 in podocytes. Journal of the American Society of Nephrology : JASN 106 21980113
2015 TRPC6 channel as an emerging determinant of the podocyte injury susceptibility in kidney diseases. American journal of physiology. Renal physiology 103 26084930
2016 TRPC6 G757D Loss-of-Function Mutation Associates with FSGS. Journal of the American Society of Nephrology : JASN 96 26892346
2005 Receptor-operated Ca2+ entry mediated by TRPC3/TRPC6 proteins in rat prostate smooth muscle (PS1) cell line. Journal of cellular physiology 92 15672411
2020 Structural basis for pharmacological modulation of the TRPC6 channel. eLife 91 32149605
2001 Muscarinic acetylcholine receptor regulation of TRP6 Ca2+ channel isoforms. Molecular structures and functional characterization. The Journal of biological chemistry 84 11278449
2008 Expression of TRPC6 channels in human epithelial breast cancer cells. BMC cancer 81 18452628
2014 TRPC6: physiological function and pathophysiological relevance. Handbook of experimental pharmacology 79 24756706
2004 Activation of human TRPC6 channels by receptor stimulation. The Journal of biological chemistry 78 15023993
2010 Canonical transient receptor potential 6 (TRPC6), a redox-regulated cation channel. The Journal of biological chemistry 75 20501650
2007 TRPC6 and FSGS: the latest TRP channelopathy. Biochimica et biophysica acta 71 17459670
2007 TRPC6. Handbook of experimental pharmacology 65 17217054
2014 Glucose specifically regulates TRPC6 expression in the podocyte in an AngII-dependent manner. The American journal of pathology 61 24731445
2023 Podocyte Injury in Diabetic Kidney Disease in Mouse Models Involves TRPC6-mediated Calpain Activation Impairing Autophagy. Journal of the American Society of Nephrology : JASN 59 37678257
2019 Role of TRPC6 in Progression of Diabetic Kidney Disease. Current hypertension reports 56 31115705
2018 Ion Channels and Transporters in Inflammation: Special Focus on TRP Channels and TRPC6. Cells 56 29973568
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
2018 Trpc6 inactivation confers protection in a model of severe nephrosis in rats. Journal of molecular medicine (Berlin, Germany) 50 29785489
2016 Synaptopodin Limits TRPC6 Podocyte Surface Expression and Attenuates Proteinuria. Journal of the American Society of Nephrology : JASN 50 27020855
2021 Novel Mechanistic Insights and Potential Therapeutic Impact of TRPC6 in Neurovascular Coupling and Ischemic Stroke. International journal of molecular sciences 49 33669830
2018 The NCX1/TRPC6 Complex Mediates TGFβ-Driven Migration and Invasion of Human Hepatocellular Carcinoma Cells. Cancer research 49 29500176
2016 Classical transient receptor potential 6 (TRPC6) channels support myofibroblast differentiation and development of experimental pulmonary fibrosis. Biochimica et biophysica acta. Molecular basis of disease 49 27932059
2012 TRPC6 inhibited NMDA receptor activities and protected neurons from ischemic excitotoxicity. Journal of neurochemistry 49 23043486
2021 TRPC6, a therapeutic target for pulmonary hypertension. American journal of physiology. Lung cellular and molecular physiology 48 34704831
2019 Metformin reduces TRPC6 expression through AMPK activation and modulates cytoskeleton dynamics in podocytes under diabetic conditions. Biochimica et biophysica acta. Molecular basis of disease 48 31778750
2018 Pyrazolo[1,5-a]pyrimidine TRPC6 antagonists for the treatment of gastric cancer. Cancer letters 47 29859875
2017 The Role of TRPC6 in the Neuroprotection of Calycosin Against Cerebral Ischemic Injury. Scientific reports 46 28596571
2010 Targeting TRPC6 channels in oesophageal carcinoma growth. Expert opinion on therapeutic targets 46 20235901
2019 Knockout of TRPC6 promotes insulin resistance and exacerbates glomerular injury in Akita mice. Kidney international 45 30665571
2013 Vitamin D down-regulates TRPC6 expression in podocyte injury and proteinuric glomerular disease. The American journal of pathology 40 23385000
2009 Expression of TRPC6 in benign and malignant human prostate tissues. Asian journal of andrology 40 19701218
2019 WNK1 promotes renal tumor progression by activating TRPC6-NFAT pathway. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 39 31022353
2015 Molecular and clinical analysis of TRPC6 and AGTR1 genes in patients with pulmonary arterial hypertension. Orphanet journal of rare diseases 39 25603901
2011 TGF-β1 induces podocyte injury through Smad3-ERK-NF-κB pathway and Fyn-dependent TRPC6 phosphorylation. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 39 21220918
2019 Transmembrane insertases and N-glycosylation critically determine synthesis, trafficking, and activity of the nonselective cation channel TRPC6. The Journal of biological chemistry 37 31266804
2018 The TRPC6-AMPK Pathway is Involved in Insulin-Dependent Cytoskeleton Reorganization and Glucose Uptake in Cultured Rat Podocytes. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 36 30453301
2017 Inhibition of TRPC6 Signal Pathway Alleviates Podocyte Injury Induced by TGF-β1. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 36 28214865
2017 TRPC6 contributes to LPS-induced inflammation through ERK1/2 and p38 pathways in bronchial epithelial cells. American journal of physiology. Cell physiology 35 29141922
2016 TRPC6 channel activation promotes neonatal glomerular mesangial cell apoptosis via calcineurin/NFAT and FasL/Fas signaling pathways. Scientific reports 33 27383564
2017 TRPC6 counteracts TRPC3-Nox2 protein complex leading to attenuation of hyperglycemia-induced heart failure in mice. Scientific reports 32 28790356
2021 The Role of TRPC6 in Renal Ischemia/Reperfusion and Cellular Hypoxia/Reoxygenation Injuries. Frontiers in molecular biosciences 31 34307458
2015 The contribution of TRPC1, TRPC3, TRPC5 and TRPC6 to touch and hearing. Neuroscience letters 29 26520460
2017 TRPC6-mediated ERK1/2 phosphorylation prevents dentate granule cell degeneration via inhibiting mitochondrial elongation. Neuropharmacology 28 28479396
2016 Second Messenger-Operated Calcium Entry Through TRPC6. Advances in experimental medicine and biology 28 27161231
2018 Increased TRPC6 expression is associated with tubular epithelial cell proliferation and inflammation in diabetic nephropathy. Molecular immunology 26 29288897
2015 The role of TRPC6 in oxidative stress-induced podocyte ischemic injury. Biochemical and biophysical research communications 26 25896763
2006 TRPC6 in glomerular health and disease: what we know and what we believe. Seminars in cell & developmental biology 26 17116414
2023 Transient Receptor Potential Canonical 6 (TRPC6) Channel in the Pathogenesis of Diseases: A Jack of Many Trades. Inflammation 25 37072606
2016 Renoprotection: focus on TRPV1, TRPV4, TRPC6 and TRPM2. Acta physiologica (Oxford, England) 25 28028935
2015 Receptor channel TRPC6 orchestrate the activation of human hepatic stellate cell under hypoxia condition. Experimental cell research 25 25845497
2021 TRPC6 Attenuates Cortical Astrocytic Apoptosis and Inflammation in Cerebral Ischemic/Reperfusion Injury. Frontiers in cell and developmental biology 23 33604333
2020 TRPC6 channel and its implications in breast cancer: an overview. Biochimica et biophysica acta. Molecular cell research 23 32822726
2017 Calcium-Sensing Receptor Stimulation in Cultured Glomerular Podocytes Induces TRPC6-Dependent Calcium Entry and RhoA Activation. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 23 29050010
2012 Dexamethasone Resisted Podocyte Injury via Stabilizing TRPC6 Expression and Distribution. Evidence-based complementary and alternative medicine : eCAM 22 22545060
2022 Pharmacological TRPC6 inhibition improves survival and muscle function in mice with Duchenne muscular dystrophy. JCI insight 21 36099033
2021 Melatonin downregulates TRPC6, impairing store-operated calcium entry in triple-negative breast cancer cells. The Journal of biological chemistry 21 33380424
2021 Effects of TRPC6 Inactivation on Glomerulosclerosis and Renal Fibrosis in Aging Rats. Cells 21 33918778
2020 The lncRNA TUG1 promotes cell growth and migration in colorectal cancer via the TUG1-miR-145-5p-TRPC6 pathway. Biochemistry and cell biology = Biochimie et biologie cellulaire 21 32985219
2022 Role of TRPC6 in periodontal tissue reconstruction mediated by appropriate stress. Stem cell research & therapy 20 35932080
2022 Mechanosensitive cation currents through TRPC6 and Piezo1 channels in human pulmonary arterial endothelial cells. American journal of physiology. Cell physiology 20 35968892
2019 High glucose reduces expression of podocin in cultured human podocytes by stimulating TRPC6. American journal of physiology. Renal physiology 20 31566428
2014 TRPC6 regulates cell cycle progression by modulating membrane potential in bone marrow stromal cells. British journal of pharmacology 20 25041367
2022 Trpc6 Promotes Doxorubicin-Induced Cardiomyopathy in Male Mice With Pleiotropic Differences Between Males and Females. Frontiers in cardiovascular medicine 19 35096991
2020 Transient receptor potential channels TRPC1/TRPC6 regulate lamina cribrosa cell extracellular matrix gene transcription and proliferation. Experimental eye research 19 32088241
2020 Novel Targets for Stroke Therapy: Special Focus on TRPC Channels and TRPC6. Frontiers in aging neuroscience 19 32256338
2020 Association of Genetic Variants at TRPC6 With Chemotherapy-Related Heart Failure. Frontiers in cardiovascular medicine 19 32903434
2020 Low-glucose-sensitive TRPC6 dysfunction drives hypoglycemia-induced cognitive impairment in diabetes. Clinical and translational medicine 19 33135341
2024 TRPC6 regulates necroptosis in myocardial ischemia/reperfusion injury via Ca2+/CaMKII signaling pathway. Cellular signalling 17 39134250
2022 TRPC6 inhibits renal tubular epithelial cell pyroptosis through regulating zinc influx and alleviates renal ischemia-reperfusion injury. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 17 36036542
2021 Cytoskeleton Rearrangements Modulate TRPC6 Channel Activity in Podocytes. International journal of molecular sciences 17 33922367
2019 The Deletion of TRPC6 Channels Perturbs Iron and Zinc Homeostasis and Pregnancy Outcome in Mice. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 17 30873821
2014 STIM1 regulates TRPC6 heteromultimerization and subcellular location. The Biochemical journal 17 25088676
2018 Permeation and Rectification in Canonical Transient Receptor Potential-6 (TRPC6) Channels. Frontiers in physiology 16 30123138
2017 Integration of TRPC6 and NADPH oxidase activation in lysophosphatidylcholine-induced TRPC5 externalization. American journal of physiology. Cell physiology 16 28835433
2015 Hyperforin: To Be or Not to Be an Activator of TRPC(6). Reviews of physiology, biochemistry and pharmacology 16 26384487
2012 TRPC6 gene variants in Czech adult patients with focal segmental glomerulosclerosis and minimal change disease. Folia biologica 16 22980509
2022 Activation of TRPC6 by AngⅡ Induces Podocyte Injury and Participates in Proteinuria of Nephrotic Syndrome. Frontiers in pharmacology 15 35991898
2022 Long noncoding RNA SNHG5 promotes podocyte injury via the microRNA-26a-5p/TRPC6 pathway in diabetic nephropathy. The Journal of biological chemistry 15 36257404
2016 Increased expression of transient receptor potential canonical 6 (TRPC6) in differentiating human megakaryocytes. Cell biology international 15 26514329
2023 Piperlonguminine attenuates renal fibrosis by inhibiting TRPC6. Journal of ethnopharmacology 14 37121453
2023 The calcium channel TRPC6 promotes chemotherapy-induced persistence by regulating integrin α6 mRNA splicing. Cell reports 14 37910503
2021 The role of TRPC6 calcium channels and P2 purinergic receptors in podocyte mechanical and metabolic sensing. Physiology international 14 34978536
2019 TRPC6 in diabetic kidney disease: good guy or bad guy? Kidney international 14 30665563
2015 TRPC6 gene variants and neuropsychiatric lupus. Journal of neuroimmunology 14 26531690
2024 Natural History and Clinicopathological Associations of TRPC6-Associated Podocytopathy. Journal of the American Society of Nephrology : JASN 13 39352759
2022 Klotho Ameliorates Podocyte Injury through Targeting TRPC6 Channel in Diabetic Nephropathy. Journal of diabetes research 13 35480629
2022 The Effects of TRPC6 Knockout in Animal Models of Kidney Disease. Biomolecules 13 36421724
2016 Insulin Increases Expression of TRPC6 Channels in Podocytes by a Calcineurin-Dependent Pathway. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 13 26849622

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