Affinage

TRPC4

Short transient receptor potential channel 4 · UniProt Q9UBN4

Length
977 aa
Mass
112.1 kDa
Annotated
2026-06-10
100 papers in source corpus 56 papers cited in narrative 57 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

TRPC4 is a Ca2+-permeable nonselective cation channel that converts G-protein-coupled receptor signaling into membrane depolarization and Ca2+ entry across vascular, smooth muscle, and neuronal tissues (PMID:11175743, PMID:10837492, PMID:19549525). The channel is activated by Gq/11-coupled receptors and receptor tyrosine kinases independently of store depletion (PMID:10837492), but its principal direct trigger is the Gi/o family — particularly Gαi2, which binds the C-terminal SESTD/CIRB region (via residues K715/R716) when the channel is open (PMID:22457348, PMID:18854172, PMID:25788576); full activation requires coincident PLCδ1 engagement and hydrolysis of PIP2 rather than store depletion or DAG alone (PMID:26755577). PIP2 exerts isoform-specific tonic inhibition of TRPC4α (but not TRPC4β) through the C-terminal PDZ-binding TRL motif that tethers the channel to the actin cytoskeleton via NHERF/EBP50 and ERM proteins; dynamic dissociation of NHERF upon PIP2 hydrolysis is a prerequisite for DAG-mediated gating, making the scaffold itself a negative regulator (PMID:18230622, PMID:27994151, PMID:30755645). Calmodulin binds two C-terminal domains in a Ca2+-dependent manner and, as resolved by cryo-EM, locks the channel closed by ordering the rib helix, while structural studies define the tetrameric six-transmembrane fold, the disulfide-stabilized pore loop, and a conserved S4-S5 linker glycine (G503) that couples to S6 residue S623 during gating (PMID:11311128, PMID:30082700, PMID:33236980, PMID:23677990). TRPC4 assembles as homotetramers or heteromultimers exclusively with TRPC1, TRPC3, and TRPC5, with the first ankyrin-like repeat and N-terminal self-association domains driving assembly and a distinct N-terminal domain (aa 23-29) plus the PDZ motif directing plasma-membrane targeting (PMID:16537542, PMID:11713258, PMID:28790178, PMID:17624425, PMID:19070363, PMID:25349210). In native tissues TRPC4 underlies store-operated Ca2+ entry in vascular endothelium required for vasorelaxation and microvascular permeability (PMID:11175743, PMID:12114324), the muscarinic cation current (mICAT) coupling muscarinic receptors to intestinal smooth muscle contraction (PMID:19549525), and Gq/11–Gi/o coincidence-detector plateau depolarizations in lateral septal and amygdala neurons as well as heteromeric TRPC1/4/5 channels supporting hippocampal synaptic transmission and working memory (PMID:28790178, PMID:24599464, PMID:35544691). A gain-of-function TRPC4-I957V variant is associated with reduced myocardial infarction risk (PMID:21427121).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 2000 High

    Establishing how TRPC4 is gated answered whether it is a store-operated channel or a receptor-operated one — TRPC4 was shown to be activated by Gq/11 receptors and RTKs independent of store depletion, defining it as a receptor-operated cation channel.

    Evidence Heterologous expression in HEK293 with patch clamp, Mn2+ quench, and GTPγS infusion

    PMID:10837492

    Open questions at the time
    • Did not identify which G-protein subunit directly couples to the channel
    • Native physiological agonists not defined
  2. 2001 High

    Knockout and antisense studies resolved whether TRPC4 contributes to native store-operated currents, establishing it as an indispensable component of endothelial SOC required for agonist-induced Ca2+ entry and vasorelaxation.

    Evidence TRPC4-/- mice and bovine adrenal antisense knockdown with electrophysiology, Ca2+ imaging, and vascular tension assays

    PMID:10816590 PMID:11175743

    Open questions at the time
    • Apparent conflict with the receptor-operated gating model not reconciled
    • Molecular composition of the native SOC complex undefined
  3. 2001 High

    Splice-variant analysis explained why TRPC4 activity varies — the TRPC4α C-terminus acts as an autoinhibitory domain whose truncation restores activity, and FRET confirmed homo- and heteromultimer assembly of α and β.

    Evidence Heterologous expression, whole-cell patch clamp, FRET, GFP-fusion trafficking in HEK293 cells

    PMID:11713258

    Open questions at the time
    • Molecular basis of the autoinhibition (lipid vs. scaffold) not yet identified
    • Physiological relevance of α/β ratio in native tissue unknown
  4. 2000 High

    Identifying scaffold partners addressed how TRPC4 is organized and localized — NHERF/EBP50 binds the channel and PLCβ, linking it to the ERM-actin cytoskeleton and forming a signaling complex in native brain.

    Evidence Reciprocal Co-IP from transfected cells and mouse brain plus GST pull-down

    PMID:10980202

    Open questions at the time
    • Functional consequence of the complex for gating not established at this stage
  5. 2001 High

    Mapping calmodulin binding addressed Ca2+-dependent feedback — TRPC4 binds CaM at two C-terminal domains in a Ca2+-dependent manner with defined affinities.

    Evidence CaM-Sepharose affinity, GST pull-down, dansyl-CaM peptide fluorimetry

    PMID:11311128

    Open questions at the time
    • Functional effect of CaM binding on channel gating not shown until structural work
    • Stoichiometry in the assembled channel unknown
  6. 2002 High

    Knockout studies extended TRPC4's endothelial role to barrier function, showing TRPC4-dependent Ca2+ entry drives actin stress-fiber formation, cell retraction, and increased lung microvascular permeability, and to pacemaker ICC where TRPC4 localizes to caveolae.

    Evidence TRPC4-/- lung endothelial cells, isolated-perfused lung filtration measurement, caveolae fractionation and Ca2+ imaging in ICC

    PMID:11897792 PMID:12114324

    Open questions at the time
    • Direct demonstration that caveolar localization gates ICC pacemaking lacking
    • Link between Ca2+ entry and cytoskeletal contraction mechanistically incomplete
  7. 2002 High

    Surface-targeting studies defined how TRPC4 reaches the plasma membrane — the C-terminal TRL PDZ motif and its EBP50/ERM interaction control membrane localization, with motif deletion causing perinuclear/Golgi retention.

    Evidence Immunofluorescence, surface biotinylation, EBP50 truncation mutants in HEK293; biophysical channel characterization in GI smooth muscle

    PMID:12154080 PMID:12388058

    Open questions at the time
    • Trafficking machinery downstream of the motif not identified
    • Relationship of TRL-dependent targeting to PIP2 inhibition not yet linked
  8. 2005 High

    Cytoskeletal anchoring partners addressed how the channel's gating machinery is assembled at the membrane — protein 4.1 and ZO-1 bind TRPC4, and protein 4.1 interaction is essential for endothelial store-operated channel gating.

    Evidence Co-IP, domain deletion, peptide competition, electrophysiology in endothelial and astrocyte systems

    PMID:15540229 PMID:16254212

    Open questions at the time
    • How spectrin-actin coupling mechanically gates the pore is unresolved
    • ZO-1 and protein 4.1 contributions to native gating in other tissues untested
  9. 2006 High

    Heteromultimer studies established TRPC4's partner specificity beyond homotetramers, showing TRPC3-TRPC4 form a redox-sensitive heteromeric channel in native endothelium.

    Evidence Co-IP, FRET, dominant-negative electrophysiology in porcine aortic endothelial cells

    PMID:16537542

    Open questions at the time
    • Physiological stimulus engaging the redox-sensitive heteromer in vivo undefined
  10. 2007 Medium

    Assembly-domain mapping answered which structural element drives tetramerization — the first ankyrin-like repeat is the minimal domain for homo/heteromeric assembly and acts dominant-negatively when expressed alone.

    Evidence FRET, TIRF, dominant-negative electrophysiology, deletion mutants in HEK293

    PMID:17624425

    Open questions at the time
    • Single lab; in vivo relevance of N-terminal assembly fragments not tested
  11. 2008 Medium

    Identifying the direct G-protein activator answered the long-standing gating question — only Gαi among tested Gα proteins directly activates TRPC4, with M2-receptor coupling blocked by pertussis toxin, distinguishing it from TRPC5/6/V6.

    Evidence Whole-cell patch clamp, pertussis toxin, constitutively active Gα and M2 co-expression in HEK293

    PMID:18854172

    Open questions at the time
    • Single method, single lab
    • Direct binding not yet demonstrated, only functional selectivity
  12. 2008 High

    Lipid-regulation studies revealed isoform-specific PIP2 control — PIP2 inhibits TRPC4α (not β) through the PDZ-motif/actin linkage, and PIP2 breakdown is a required activation step alongside Ca2+ and Gi/o.

    Evidence Patch clamp with intracellular PIP2, in vitro lipid binding, cytochalasin D, PDZ-deletion mutants

    PMID:18230622

    Open questions at the time
    • Direct PIP2 binding residues not yet mapped
    • How cytoskeletal tethering transduces lipid signal to the gate unclear
  13. 2012 High

    Mapping the Gαi interface answered how Gi/o coupling occurs structurally — Gαi2 directly binds the C-terminal SESTD domain via K715/R716 and fully activates the channel.

    Evidence Co-IP, site-directed mutagenesis, constitutively active Gαi2, patch clamp, Ca2+ imaging

    PMID:22457348

    Open questions at the time
    • Stoichiometry of Gαi2:channel interaction undefined
    • Coupling to receptor identity in different native tissues incompletely mapped
  14. 2013 Medium

    Gating-residue and gain-of-function studies defined the pore-coupling mechanism — S4-S5 linker glycine G503 couples to S6 S623, and a TRPC4-I957V variant associated with reduced MI risk shows enhanced activity.

    Evidence Site-directed mutagenesis with gain-of-function electrophysiology and homology modeling; HEK293/CHO functional studies of the SNP

    PMID:21427121 PMID:23677990

    Open questions at the time
    • G503-S623 coupling inferred from mutagenesis prior to structure
    • I957V genetic association is correlative for disease risk
  15. 2016 High

    Coincidence-detection studies integrated the activation logic — TRPC4 requires coincident Gi/o and PLCδ1 signaling with PIP2, and dynamic NHERF1/2 dissociation upon PIP2 hydrolysis is the prerequisite for DAG sensitivity, making the scaffold a direct negative regulator.

    Evidence Patch clamp, PLCδ1 siRNA, dominant-negative and constitutively active constructs, FRET conformational analysis, PDZ-motif mutagenesis

    PMID:26755577 PMID:27994151

    Open questions at the time
    • Exact conformational path from C-terminus to pore not resolved at this stage
    • Generalizability of the PLCδ1 requirement across native tissues untested
  16. 2017 High

    Native interactome and triple-KO behavior established TRPC4's neuronal partner identity and physiology — TRPC1/4/5 assemble exclusively with one another in brain and support hippocampal synaptic transmission and spatial working memory.

    Evidence Quantitative mass spectrometry interactome, triple-KO hippocampal slice electrophysiology, in vivo LFP, behavior

    PMID:28790178

    Open questions at the time
    • Subunit stoichiometry of native TRPC1/4/5 channels undefined
    • Receptor coupling driving synaptic TRPC currents not fully mapped
  17. 2018 High

    Cryo-EM structures answered the architecture question — TRPC4 is a tetrameric six-transmembrane channel with a disulfide-stabilized pore loop, defined selectivity filter and lower gate, and cytoplasmic hubs for protein interactions.

    Evidence Cryo-EM of mouse (3.3 Å) and zebrafish (3.6 Å) TRPC4

    PMID:29717981 PMID:30082700

    Open questions at the time
    • Closed/apo states only; activated-state structure not captured
    • Direct visualization of lipid and G-protein binding not yet achieved
  18. 2020 High

    Ligand-bound cryo-EM revealed the CaM-mediated closing mechanism and a drug-binding pocket — CaM binds the rib helix to fix the channel closed, and pyridazinone inhibitors bind a voltage-sensing-like-domain cavity that propagates to the pore.

    Evidence Cryo-EM of TRPC4-CaM and TRPC4-inhibitor complexes

    PMID:33236980

    Open questions at the time
    • How physiological Ca2+/CaM dynamics tune gating in vivo not established
    • Structure of the activating PIP2/Gαi-bound state still absent
  19. 2022 High

    Neuronal recordings refined TRPC4 as a bidirectional coincidence sensor — in lateral septal neurons it integrates Gq/11 (mGluR) and Gi/o (GABAB) inputs into plateau depolarizations, with GIRK encoding the relative input strengths as firing patterns.

    Evidence Whole-cell slice recordings, receptor pharmacology, TRPC4-/- mice, computational modeling

    PMID:35544691

    Open questions at the time
    • Molecular determinants distinguishing coincidence detection across neuron types unclear
    • In vivo behavioral correlate of the encoding scheme untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the activating conformation is achieved at the structural level — the simultaneous engagement of Gαi2, PIP2 depletion, PLCδ1, NHERF dissociation, and Ca2+/CaM converging on the G503-S623 gate — remains unresolved, as all available high-resolution structures are closed or inhibitor-bound.
  • No open-state structure of TRPC4
  • No reconstitution combining G-protein, lipid, and scaffold inputs
  • Subunit stoichiometry of native heteromers undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 4 GO:0060089 molecular transducer activity 4 GO:0008289 lipid binding 2
Localization
GO:0005886 plasma membrane 5 GO:0005856 cytoskeleton 3 GO:0005783 endoplasmic reticulum 1 GO:0005794 Golgi apparatus 1
Pathway
R-HSA-112316 Neuronal System 5 R-HSA-162582 Signal Transduction 4 R-HSA-382551 Transport of small molecules 3 R-HSA-397014 Muscle contraction 1
Partners
CALM1GNAI2NHERF1SESTD1STIM1TRPC1TRPC3TRPC5
Complex memberships
TRPC1/4 heteromeric channelTRPC1/4/5 heteromeric channelTRPC3/4 redox-sensitive heteromeric channelTRPC4-NHERF/EBP50 scaffold complex

Evidence

Reading pass · 57 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 TRP4-deficient (TRPC4-/-) mice lack a store-operated Ca2+ current in vascular endothelial cells, establishing that TRP4 is an indispensable component of store-operated channels in native endothelial cells and that these channels are required for agonist-induced Ca2+ entry and vasorelaxation. Knockout mouse model, electrophysiology, Ca2+ imaging, vascular tension measurements Nature cell biology High 11175743
2000 Murine TRPC4 forms a nonselective cation channel activated by Gq/11-coupled receptors and receptor tyrosine kinases independently of intracellular Ca2+ store depletion; single-channel conductance is 42 pS at -60 mV; store depletion alone fails to activate the channel. Heterologous expression in HEK293 cells, whole-cell and inside-out patch clamp, Mn2+ quench fluorimetry, GTPγS infusion The Journal of biological chemistry High 10837492
2000 Murine TRP4 and phospholipase Cβ1/β2 interact with the first PDZ domain of the scaffolding protein NHERF (EBP50), and TRP4/PLCβ1/NHERF complexes co-immunoprecipitate from HEK293-Trp4 cells and adult mouse brain, linking the channel to the actin cytoskeleton via the ERM-NHERF interaction. Co-immunoprecipitation from transfected cells and native brain tissue, GST pull-down The Journal of biological chemistry High 10980202
2000 TRP4 protein is abundantly expressed in bovine adrenal cortex cells and contributes essentially to native CRAC-like (store-operated) currents; antisense reduction of TRP4 protein significantly reduces both endogenous CRAC-like currents and native TRP4 protein. Antisense knockdown, Northern blot, immunoblot, immunohistochemistry, electrophysiology The Journal of biological chemistry High 10816590
2002 TRPC4-/- lung endothelial cells show drastically reduced agonist (thrombin/PAR-1)-induced Ca2+ influx, lack actin stress fiber formation and cell retraction, and isolated-perfused TRPC4-/- lungs show markedly attenuated increases in microvascular permeability, establishing TRPC4-dependent Ca2+ entry as a key determinant of increased microvascular permeability. TRPC4 knockout mouse model, Ca2+ imaging, actin staining, isolated-perfused lung microvascular filtration coefficient measurement Circulation research High 12114324
2001 TRP4 directly binds calmodulin (CaM) in a Ca2+-dependent manner through two C-terminal domains (residues 688-759 and 786-848); half-maximal CaM binding occurs at 16.6 µM (domain 1) and 27.9 µM (domain 2) Ca2+; synthetic peptides from these regions bind dansyl-CaM with Kd 94-189 nM. CaM-Sepharose affinity chromatography, GST pull-down, synthetic peptide binding assay with dansyl-CaM fluorimetry The Biochemical journal High 11311128
2006 TRPC3 and TRPC4 associate to form a redox-sensitive heteromeric cation channel complex in porcine aortic endothelial cells; co-IP demonstrates physical association; FRET shows close proximity between TRPC4 N-terminus and TRPC3 C-terminus; dominant-negative TRPC4 suppresses TRPC3-related currents and the native redox-sensitive conductance. Co-immunoprecipitation, FRET, whole-cell electrophysiology, dominant-negative expression The Journal of biological chemistry High 16537542
2009 In intestinal smooth muscle cells, TRPC4 forms a 55 pS cation channel underlying >80% of muscarinic receptor-induced cation current (mICAT); TRPC4-deficient myocytes show greatly reduced carbachol-induced membrane depolarization; TRPC4/C6 double KO slows intestinal transit in vivo, establishing TRPC4 and TRPC6 as the molecular basis of mICAT coupling muscarinic receptors to smooth muscle contraction. Single and double knockout mice, whole-cell patch clamp, muscle contraction assays, intestinal transit measurement Gastroenterology High 19549525
2008 TRPC4α (but not TRPC4β) is strongly inhibited by intracellularly applied PIP2 in an isoform-specific manner; PIP2 binds to the C-terminus of TRPC4α but not TRPC4β in vitro; inhibition requires association with actin cytoskeleton via the C-terminal PDZ-binding motif (Thr-Thr-Arg-Leu) that links TRPC4 to F-actin through NHERF and ezrin; PIP2 breakdown is a required step in TRPC4α activation requiring additional Ca2+ and Gi/o proteins. Whole-cell patch clamp with intracellular PIP2 application, in vitro lipid-binding assay, cytochalasin D treatment, PDZ-motif deletion mutants The Journal of biological chemistry High 18230622
2001 Human TRPC4α contains a C-terminal autoinhibitory domain: TRPC4β is robustly activated by receptor stimulation across species, whereas TRPC4α shows poor activation; C-terminal truncation of TRPC4α fully restores channel activity; TRPC4α exerts a dominant-negative effect on TRPC4β with cooperativity >2 in heteromultimers; FRET confirms homomultimer and heteromultimer assembly of TRPC4α and TRPC4β. Heterologous expression, whole-cell patch clamp, FRET in living cells The Journal of biological chemistry High 11713258
2005 Protein 4.1 interacts with TRPC4 and the spectrin-actin membrane skeleton; deletion of the protein 4.1 binding domain on TRPC4 or peptide competition to this domain prevents activation of the endothelial ISOC (store-operated) channel, establishing protein 4.1 interaction with TRPC4 as an essential component of the ISOC gating mechanism. Co-immunoprecipitation, domain deletion, peptide competition, whole-cell electrophysiology Circulation research High 16254212
2002 The PDZ-interacting TRL motif at the TRPC4 C-terminus controls its plasma membrane localization; deletion of TRL causes accumulation in cell outgrowths and reduces plasma membrane expression ~2.4-fold; co-expression with an EBP50 mutant lacking the ERM-binding site retains TRPC4 in a perinuclear (Golgi) compartment. Immunofluorescence microscopy, cell surface biotinylation, co-expression with EBP50 truncation mutants in HEK293 cells Journal of cell science High 12154080
2012 Gαi subunits, particularly Gαi2, are primary and direct activators of TRPC4, acting through direct interaction with the conserved C-terminal SESTD domain; Gαi2 activation by muscarinic M2 receptors or constitutively active Gαi2 mutants fully activates the channel; two amino acids (K715 and R716) in the TRPC4 C-terminus mediate the interaction with Gαi2. Co-immunoprecipitation, whole-cell patch clamp, constitutively active Gα mutant expression, site-directed mutagenesis, Ca2+ imaging The Journal of biological chemistry High 22457348
2016 TRPC4 activation requires coincident stimulation of Gi/o proteins and PLCδ1 (preferentially over PLCβ); PIP2 is required for biphasic TRPC4 activation; reducing PIP2 via phosphatases abolishes biphasic kinetics; dominant-negative PLCδ1 or constitutively active RhoA almost completely eliminates TRPC4 activation; this mechanism differs from the closely related TRPC5. Whole-cell patch clamp, siRNA knockdown of PLCδ1, dominant-negative constructs, constitutively active RhoA, PIP2 manipulation in HEK293 and A-498 renal carcinoma cells Proceedings of the National Academy of Sciences of the United States of America High 26755577
2016 Dynamic interaction of NHERF1/2 with the C-terminal PDZ-binding motif of TRPC4/5 suppresses DAG sensitivity; PIP2 depletion evokes a C-terminal conformational change leading to NHERF dissociation, which is a prerequisite for DAG-mediated channel activation; PKC inhibition or PDZ-motif mutation confers DAG sensitivity, establishing NHERF as a direct negative regulator of TRPC4/5 DAG sensitivity. Whole-cell patch clamp, FRET-based conformational analysis, PKC inhibition, site-directed mutagenesis of PDZ-binding motif Proceedings of the National Academy of Sciences of the United States of America High 27994151
2018 Cryo-EM structure of mouse TRPC4 at 3.3 Å resolution reveals a unique architecture with a long pore loop stabilized by a disulfide bond, a unique cytosolic N-terminal domain forming extensive aromatic contacts with the TRP and C-terminal domains, and a tetrameric six-transmembrane fold; structural features provide molecular basis for TRPC4 ion selectivity. Cryo-electron microscopy, 3.3 Å resolution structure determination Nature communications High 30082700
2018 Cryo-EM structure of zebrafish TRPC4 at 3.6 Å resolution in unliganded closed state reveals molecular architecture of the cation-conducting pore including selectivity filter and lower gate; cytoplasmic domain contains two key hubs for modulating protein interactions. Cryo-electron microscopy, 3.6 Å resolution structure determination eLife High 29717981
2020 Cryo-EM structures of TRPC4 in complex with calmodulin and three pyridazinone inhibitors reveal that all inhibitors bind to the same cavity in the voltage-sensing-like domain; structural changes propagate from the ligand-binding site to the central ion-conducting pore; CaM binds to the rib helix of TRPC4, ordering a previously disordered region and fixing the channel in a closed conformation — a novel CaM-induced regulatory mechanism. Cryo-EM structural determination of TRPC4-CaM and TRPC4-inhibitor complexes eLife High 33236980
2017 TRPC1, TRPC4, and TRPC5 assemble exclusively into heteromultimers with each other (not other TRP family members) in mouse brain, as shown by quantitative mass spectrometry; TRPC1/4/5 triple-KO hippocampal neurons show significantly reduced action potential-triggered EPSCs and impaired hippocampal network cross-frequency coupling and spatial working memory, establishing heteromultimeric TRPC1/4/5 channels as regulators of hippocampal synaptic transmission. Quantitative high-resolution mass spectrometry for interactome, triple-knockout mouse model, hippocampal slice electrophysiology, in vivo LFP recording, behavioral testing The EMBO journal High 28790178
2015 TRPC1/TRPC4 double-KO mice show reduced background Ca2+ entry (BGCE) in cardiomyocytes, lower diastolic and systolic Ca2+ concentrations, and are protected against neurohumoral-induced and pressure overload-induced cardiac hypertrophy and fibrosis; TRPC1 or TRPC4 single-KO mice do not show protection, establishing a cooperative TRPC1/C4 constitutively active BGCE pathway as a driver of pathological cardiac remodeling. Multiple knockout mouse models, fluorescence Ca2+ imaging of electrically paced cardiomyocytes, Mn2+ quench microfluorimetry, cardiac hypertrophy models (neurohumoral, pressure overload) European heart journal High 26069213
2001 The alpha1 and beta2 splice variants of human TRPC4 differ in regulation: hTRPC4β forms receptor-operated cation channels when expressed in HEK293 cells, while hTRPC4α is poorly activated by H1 receptor stimulation despite correct plasma membrane targeting; the C-terminal region of hTRPC4α acts as an autoinhibitory domain, as C-terminal truncation fully restores channel activity. Heterologous expression, whole-cell patch clamp, FRET, GFP-fusion protein trafficking The Journal of biological chemistry High 11713258
2002 TRP4 is localized to caveolae of interstitial cells of Cajal (ICC); Ca2+ oscillations in ICC depend on Ca2+ influx through a non-selective, store-operated, SK&F 96365-sensitive cation channel; this links TRP4 localization in caveolae to pacemaker Ca2+ oscillations in ICC. Immunofluorescence/caveolae fractionation, Ca2+ imaging with fluo-4, pharmacological inhibition, c-Kit immunoreactivity for ICC identification The Journal of biological chemistry Medium 11897792
2001 Alpha-hTRP4 (but not beta-hTRP4) C-terminus associates in vitro with the C-terminal domain of InsP3 receptors types 1, 2, and 3, as demonstrated by yeast two-hybrid and GST pull-down; this interaction is regulated by alternative splicing (the 84 aa insert in alpha absent in beta contains the binding region). Yeast two-hybrid assay, GST pull-down experiments FEBS letters Medium 11163362
2005 TRPC4 co-localizes with and co-immunoprecipitates with ZO-1 in human fetal astrocytes via the C-terminal TRL PDZ-binding motif; deletion of TRL retains TRPC4 in a juxtanuclear compartment and reduces plasma membrane expression, demonstrating that TRPC4's PDZ-binding motif controls its surface localization in astrocytes. Co-immunoprecipitation, confocal microscopy, immunoelectron microscopy, cell surface biotinylation, GST fusion protein binding assay, TRL-motif deletion mutants Glia Medium 15540229
2009 TRPC1 and TRPC4 channels are expressed at the sarcolemma of skeletal myotubes and associate with the alpha1-syntrophin–dystrophin complex (DAPC); siRNA silencing of alpha1-syntrophin dysregulates cation influx; deletion of the PDZ-containing domain of alpha1-syntrophin prevents restoration of normal cation entry; TRPC1 and TRPC4 co-immunoprecipitate with alpha1-syntrophin, establishing DAPC-anchored TRPC1/C4 as regulators of cation homeostasis in skeletal muscle. Co-immunoprecipitation, siRNA knockdown, Ca2+ entry measurements, dominant-negative constructs The Journal of biological chemistry Medium 19812031
2009 STIM1 interacts with TRPC4 (but not TRPC1) as demonstrated by co-immunoprecipitation in human mesangial cells; TRPC1/TRPC4 complexes constitute functional SOC subunits; STIM1 knockdown significantly reduces thapsigargin-stimulated membrane currents; simultaneous inhibition of STIM1 and TRPC1 produces no additive effect on SOC over single inhibition, suggesting they act in the same pathway. Co-immunoprecipitation, siRNA knockdown, patch clamp, Ca2+ imaging Experimental biology and medicine (Maywood, N.J.) Medium 19307462
2010 SESTD1, a protein containing a SEC14-like lipid-binding domain and spectrin-type cytoskeleton interaction domains, associates with TRPC4 and TRPC5 via the channel's calmodulin- and IP3-receptor-binding (CIRB) domain; SESTD1 binds several phospholipid species in a Ca2+-dependent manner in vitro and is essential for efficient receptor-mediated activation of TRPC5. Yeast two-hybrid screen, co-immunoprecipitation, in vitro phospholipid binding, functional expression assays The Journal of biological chemistry Medium 20164195
2013 A conserved glycine residue in the cytosolic S4-S5 linker (G503 in TRPC4) is a critical gating element; TRPC4G503S mutant is constitutively active with current-voltage relationships resembling fully activated WT; a second mutation S623A in the predicted S6 helix suppresses constitutive activation, indicating that the S4-S5 linker interacts with S6 during gating. Site-directed mutagenesis, whole-cell patch clamp, homology modeling The Journal of biological chemistry High 23677990
2008 Gαi protein (specifically Gαi subtype) directly activates TRPC4 channel; among Gα proteins tested, only Gαi activates TRPC4; co-expression with M2 muscarinic receptor induces TRPC4 activation by carbachol that is blocked by pertussis toxin; this selectivity distinguishes TRPC4 from TRPC5, TRPC6, and TRPV6. Whole-cell patch clamp, pertussis toxin inhibition, co-expression with M2 receptor and constitutively active Gα constructs in HEK293 cells Biochemical and biophysical research communications Medium 18854172
2015 Gαi2 directly binds to TRPC4 when the channel is open, as demonstrated by FRET between TRPC4β-CFP and constitutively active Gαi2-YFP (~15% efficiency vs. ~5% for WT Gαi2); carbachol application via M2 receptor increases FRET efficiency between TRPC4 and Gαi2; Gβγ shows low FRET with TRPC4. FRET (CFP/YFP-tagged constructs), whole-cell patch clamp, Ca2+ imaging with YC6.1 American journal of physiology. Cell physiology Medium 25788576
2007 The first ankyrin-like repeat of TRPC4/TRPC5 is the minimum structural domain required for homo- and heteromeric channel assembly; N-terminal fragments including the first ankyrin-like repeat potently suppress TRPC4/5 currents in a dominant-negative fashion; a TRPC5 mutant lacking the first ankyrin-like repeat fails to homo-multimerise and forms non-functional channels. FRET, TIRF microscopy, dominant-negative electrophysiology in HEK293 cells, deletion mutant analysis Cell calcium Medium 17624425
2008 The N-terminus of TRPC4 self-associates and forms a tetramer; two distinct self-association domains exist in the N-terminus: the ankyrin repeat domain and the region downstream from the coiled-coil domain, both of which can self-associate independently. Size-exclusion chromatography, GST pull-down, yeast two-hybrid, circular dichroism Cell calcium Medium 19070363
2014 Deletion of TRPC4 (constitutive or lentiviral RNAi in lateral amygdala) decreases anxiety-like behavior; lateral amygdala neurons from TRPC4-/- mice lack potentiation responses through Gαq/11-coupled Group I metabotropic glutamate receptors and CCK2 receptors, establishing TRPC4 as a required component of these Gαq/11-mediated depolarizing responses in the amygdala. TRPC4-/- mice, lentiviral RNAi, brain slice electrophysiology, behavioral testing (elevated plus maze, open field) The Journal of neuroscience High 24599464
2014 In lateral septal (LS) neurons, TRPC4-containing channels mediate both below-threshold depolarization (BTD) and above-threshold plateau depolarization (ATPD) in response to group I mGluR agonist; both responses are absent in TRPC4-/- mice; ATPD requires coincident mGluR stimulation and depolarization, and depends on Na+ and Ca2+ influx with dynamic intracellular Ca2+ changes. TRPC4-/- mice, whole-cell slice recordings, pharmacological manipulation of intracellular Ca2+ and ion gradients Pflugers Archiv : European journal of physiology Medium 24121765
2022 TRPC4 acts as a coincidence sensor for Gq/11 and Gi/o signals in lateral septal neurons: group I mGluR (Gq/11) plus GABAB (Gi/o) co-activation is required for strong TRPC4-mediated plateau depolarization; GIRK channels mediate subsequent hyperpolarization; the combination of TRPC4 and GIRK conductances encodes the relative strengths of Gq/11 vs. Gi/o inputs as distinct firing patterns. Whole-cell slice recordings in lateral septal neurons, receptor agonist/antagonist pharmacology, TRPC4-/- mice, computer modeling Proceedings of the National Academy of Sciences of the United States of America High 35544691
2013 Kisspeptin activation of TRPC4α channels in GnRH neurons requires PIP2 hydrolysis (application of DiC8-PIP2 inhibits current; wortmannin prolongs activation), and cSrc tyrosine kinase activity (inhibition by genistein or PP2 blocks activation); channel activation is not store-operated (thapsigargin and IP3 have no effect) and PKC-independent. Whole-cell patch clamp in GnRH neurons, single-cell RT-PCR (TRPC4α identification), pharmacological dissection with kinase inhibitors, PIP2 dialysis, PKC activators/inhibitors Endocrinology Medium 23744639
2009 Cell-cell contact formation regulates TRPC4 surface expression and Ca2+ signaling in endothelial cells; TRPC4 co-precipitates with β-catenin and VE-cadherin; β-catenin promotes TRPC4 function in a cell-cell contact-dependent manner; EGF recruits TRPC4 to the plasma membrane in proliferating cells but causes retrieval in quiescent barrier-forming cells. Co-immunoprecipitation, siRNA knockdown, dominant-negative expression, Ca2+ imaging, fluorescent fusion protein localization in HMEC-1 and HEK293 cells The Journal of biological chemistry Medium 19996314
2007 TRPC4 knockdown by siRNA or antisense in DRG neurons significantly reduces neurite length; this is rescued by overexpression of human TRPC4, establishing a required role for TRPC4 in neurite outgrowth/axonal regeneration. siRNA and antisense knockdown, neurite length measurement, rescue by hTRPC4 overexpression in DRG neurons and ND7/23 cells The Journal of biological chemistry Medium 17928298
2004 ATP-induced CREB phosphorylation precedes and is required for TRPC4 protein upregulation in human pulmonary artery smooth muscle cells (PASMCs); transfection of a non-phosphorylatable CREB mutant abolishes ATP-mediated TRPC4 expression; TRPC4 siRNA attenuates ATP-enhanced capacitative Ca2+ entry and inhibits ATP-induced PASMC proliferation, placing CREB upstream of TRPC4 in a mitogenic signaling pathway. CREB phosphorylation assay, non-phosphorylatable CREB mutant transfection, siRNA knockdown, CCE measurement, [3H]thymidine incorporation American journal of physiology. Cell physiology Medium 15229105
2015 (-)-Englerin A is a potent, selective, direct activator of TRPC4 and TRPC5 channels; TRPC4 expression is necessary and sufficient for englerin A-induced Ca2+ influx, membrane depolarization, and growth inhibition; englerin A-induced current and growth inhibition are blocked by the TRPC4/C5 inhibitor ML204. Electrophysiology, Ca2+ imaging, genetic knockdown and overexpression, ML204 pharmacological rescue PloS one High 26098886
2017 (-)-Englerin A cytotoxicity in synovial sarcoma cells is mediated by heteromeric TRPC4/TRPC1 channels; depletion of TRPC1 converts the current to homomeric TRPC4 biophysical properties; Na+ loading through the channel mediates cytotoxicity; depletion of either TRPC1 or TRPC4 suppresses EA cytotoxicity. Whole-cell patch clamp, siRNA depletion of TRPC1 and TRPC4, Na+-loading with gramicidin-A, selective pharmacological inhibitors (Pico145 vs. ML204) Scientific reports Medium 29209034
2015 Intracellular spermine blocks TRPC4 (and TRPC5) but not TRPC1/4, TRPC1/5, or TRPC3 channels; the blocking mechanism is electrostatic interaction with glutamate residues E728 and E729 at the C-terminus of TRPC4. Whole-cell patch clamp with intracellular spermine, site-directed mutagenesis of E728/E729 Pflugers Archiv : European journal of physiology Medium 26631167
2001 TRPC4 is necessary for activation of CFTR Cl- current in mouse aortic endothelial cells; a phosphorylating cocktail activates CFTR-like Cl- current in trp4+/+ but not in trp4-/- cells, despite unchanged CFTR expression, suggesting TRP4 provides a scaffold for functional CFTR channel formation. TRPC4 knockout mouse endothelial cells, whole-cell patch clamp, RT-PCR for CFTR expression BMC physiology Medium 11356184
2007 TRPC4 knockdown reduces EGF-induced store-operated channel (SOC) activation and Ca2+ entry in human corneal epithelial cells; TRPC4 siRNA (89% mRNA knockdown) eliminates EGF-induced SOC activity and reduces EGF-induced proliferation by 54%, establishing TRPC4 as a component of SOC required for EGF mitogenic responses. siRNA knockdown, whole-cell patch clamp, Ca2+ fluorescence imaging, [3H]thymidine incorporation The Journal of biological chemistry Medium 16033767
2007 NO/cGMP/PKG-1α signaling inhibits TRPC4-SOC activity in mesangial cells; PKG-phosphorylated VASP (P-Ser239) co-immunoprecipitates with TRPC4, while unphosphorylated VASP does not, identifying phospho-VASP as a state-dependent interaction partner mediating PKG-dependent inhibition of TRPC4. Co-immunoprecipitation, immunocytochemistry, Ca2+ imaging (fura-2), PKG-1α inhibitor DT-3, 8-Br-cGMP treatment, Western blot for P-VASP American journal of physiology. Renal physiology Medium 17913834
2018 PC1 (polycystin-1) activates TRPC4 through Gαi3; Gαi3 selectively binds to the G-protein-binding domain of PC1 C-terminus; PC1 cleavage dissociates Gαi3, increasing TRPC4 activity; Ca2+ influx through TRPC4 activates STAT1 to regulate cell proliferation/death; PC1/TRPC4/STAT1 downregulation disrupts endothelial cell migration and increases permeability. Co-immunoprecipitation, TRPC4 activity measurements, STAT1 activation assay, cell migration and permeability assays, siRNA knockdown Scientific reports Medium 29472562
2014 A TRPC4 membrane-targeting domain (residues 23-29 in the N-terminus) distinct from the tetramerization domain (requiring residues downstream of aa99 in N-term and upstream of aa730 in C-term) is identified; deletion of the 23-29 region causes ER retention; FRET mapping distinguishes assembly domains from trafficking domains. Deletion mutant construction, FRET, co-expression with WT TRPC4, confocal microscopy in HEK293 cells The Journal of biological chemistry Medium 25349210
2019 PI(4,5)P2 dephosphorylation (by voltage-sensing phosphatase DrVSP) inhibits TRPC4α, TRPC4β, TRPC5 homotetramers and TRPC1/4α, TRPC1/4β, TRPC1/5 hetetrotramers; sensitivity to PI(4,5)P2 depletion increases TRPC4β < TRPC4α < TRPC5 in homotetramers; TRPC1 incorporation equalizes PI(4,5)P2 sensitivity; putative PI(4,5)P2 binding sites are identified at K419, K664/R511, K518, and H630 by mutagenesis. Danio rerio VSP-based PI(4,5)P2 depletion, patch clamp, FRET with PI(4,5)P2 sensor, mutagenesis of basic residues Scientific reports Medium 30755645
2002 TRPC4 channels in GI smooth muscle are Ca2+-inhibited nonselective cation channels; TRPC4β single-channel conductance is 17.5 pS; calmidazolium increases inward current; currents are sensitive to lanthanum, niflumic acid, and DIDS; TRPC4β properties match the ICC pacemaker current. Heterologous expression, whole-cell and single-channel patch clamp, BAPTA dialysis, N-methyl-D-glucamine replacement experiments American journal of physiology. Cell physiology Medium 12388058
2004 TRPC4 co-interacts with NHERF-2 in rat descending vasa recta (DVR); TRPC4 co-immunoprecipitates with NHERF-2 from renal medullary lysates and proteins co-localize in DVR endothelial cells and pericytes; TRPC5 is not detected in DVR. RT-PCR, immunohistochemistry, co-immunoprecipitation from native renal medullary tissue American journal of physiology. Cell physiology Medium 15590898
2022 Tricyclic antidepressants (TCAs) directly inhibit TRPC4 channels in heterologous expression (HEK293) and in native murine colonic myocytes; TCA inhibition of muscarinic cationic current (mIcat) is reduced in TRPC4-knockout mice; TCA treatment inhibits colonic motility in human tissue strips, connecting TRPC4 inhibition to TCA-induced constipation. Patch clamp in HEK293 cells and native colonic myocytes, TRPC4-KO mice, muscle contraction recordings in human colonic strips Journal of cellular and molecular medicine Medium 35560982
2020 TRPC4 and TRPC5 channels support persistent firing in CA1 pyramidal neurons; extracellular application of TRPC4 blocker ML204, TRPC5 blocker clemizole, or pan-TRPC4/5 blocker Pico145 significantly inhibits cholinergically-induced persistent firing; intracellular application of TRPC4 or TRPC5 antibodies also reduces persistent firing. Whole-cell patch clamp in CA1 neurons, selective pharmacological blockers applied extracellularly and intracellularly Cells Medium 32033274
2013 TRPC1 and TRPC4 are required for normal myotube size during human post-natal myogenesis; siRNA knockdown or dominant-negative TRPC overexpression reduces SOCE, impairs MEF2 expression, and reduces myotube size; overexpression of STIM1 with TRPC4 or TRPC1 increases SOCE and produces hypertrophic myotubes; normalization of SOCE by extracellular Ca2+, STIM1, or Orai1 overexpression does not rescue the fusion defect without TRPC channel re-expression, indicating TRPC-specific signaling requirements. siRNA knockdown, dominant-negative overexpression, SOCE measurement, MEF2 expression assay, myotube size quantification Journal of cell science Medium 23549783
2017 TRPC1 and TRPC4 interact preferentially with STIM1L (muscle-specific long isoform) over STIM1 upon store depletion; STIM1L and TRPC1/4 knockdown produce similar reductions in SOCE (~50%) and similar delays in Ca2+ entry onset; STIM1L knockdown produces smaller myotubes similar to TRPC1/4 knockdown. Co-immunoprecipitation (interaction preference), siRNA knockdown, SOCE measurement, myotube differentiation assay Biochimica et biophysica acta. Molecular cell research Medium 28185894
2013 TRPC1 and TRPC4 are required for cystitis-induced sensory neuron sprouting into the bladder mucosa; cyclophosphamide-treated Trpc1/c4-/- mice show no increased bladder innervation and diminished bladder overactivity, establishing TRPC1/C4 as necessary for injury-induced neuronal sprouting. Double knockout mice, cyclophosphamide cystitis model, immunohistochemistry for nerve fiber density, urodynamics PloS one Medium 23922735
2014 TRPC4 upregulation increases intracellular Ca2+ concentration, which activates the Ca2+/CaMKKβ/AMPK pathway leading to mTOR inhibition and autophagy induction in vascular endothelial cells; TRPC4 siRNA abrogates TMS-induced autophagy. DNA microarray, siRNA knockdown of TRPC4, TRPC4 overexpression, Ca2+ imaging, CaMKKβ/AMPK/mTOR pathway analysis Biochimica et biophysica acta Medium 25476892
2011 A gain-of-function SNP TRPC4-I957V is associated with reduced myocardial infarction risk; functional studies show TRPC4-I957V has increased channel activity and Ca2+ signals in response to muscarinic agonists and direct G-protein activation; molecular modeling suggests I957V allows firmer interaction between TRPC4 and a tyrosine kinase that phosphorylates Y959, facilitating plasma membrane insertion. Patch clamp and intracellular Ca2+ measurements in transfected HEK293/CHO cells, site-directed mutagenesis, molecular modeling Cardiovascular research Medium 21427121

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 Lack of an endothelial store-operated Ca2+ current impairs agonist-dependent vasorelaxation in TRP4-/- mice. Nature cell biology 480 11175743
2000 Receptor-mediated regulation of the nonselective cation channels TRPC4 and TRPC5. The Journal of biological chemistry 348 10837492
2002 Impairment of store-operated Ca2+ entry in TRPC4(-/-) mice interferes with increase in lung microvascular permeability. Circulation research 311 12114324
2000 Association of mammalian trp4 and phospholipase C isozymes with a PDZ domain-containing protein, NHERF. The Journal of biological chemistry 195 10980202
2010 C. elegans TRP family protein TRP-4 is a pore-forming subunit of a native mechanotransduction channel. Neuron 186 20696377
2011 Identification of ML204, a novel potent antagonist that selectively modulates native TRPC4/C5 ion channels. The Journal of biological chemistry 177 21795696
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
2000 TRP4 (CCE1) protein is part of native calcium release-activated Ca2+-like channels in adrenal cells. The Journal of biological chemistry 164 10816590
2015 (-)-Englerin A is a potent and selective activator of TRPC4 and TRPC5 calcium channels. Angewandte Chemie (International ed. in English) 163 25707820
2002 Calcium oscillation linked to pacemaking of interstitial cells of Cajal: requirement of calcium influx and localization of TRP4 in caveolae. The Journal of biological chemistry 158 11897792
2009 Deletion of TRPC4 and TRPC6 in mice impairs smooth muscle contraction and intestinal motility in vivo. Gastroenterology 146 19549525
2007 Corticolimbic expression of TRPC4 and TRPC5 channels in the rodent brain. PloS one 143 17593972
2008 Isoform-specific inhibition of TRPC4 channel by phosphatidylinositol 4,5-bisphosphate. The Journal of biological chemistry 139 18230622
2003 TRPC4 and TRPC5: receptor-operated Ca2+-permeable nonselective cation channels. Cell calcium 133 12765689
2018 Structure of the mouse TRPC4 ion channel. Nature communications 113 30082700
2018 Treatment with HC-070, a potent inhibitor of TRPC4 and TRPC5, leads to anxiolytic and antidepressant effects in mice. PloS one 110 29385160
2017 Heteromeric channels formed by TRPC1, TRPC4 and TRPC5 define hippocampal synaptic transmission and working memory. The EMBO journal 109 28790178
2000 Cloning and expression of the human transient receptor potential 4 (TRP4) gene: localization and functional expression of human TRP4 and TRP3. The Biochemical journal 107 11042129
2002 The PDZ-interacting domain of TRPC4 controls its localization and surface expression in HEK293 cells. Journal of cell science 99 12154080
2016 Dynamic NHERF interaction with TRPC4/5 proteins is required for channel gating by diacylglycerol. Proceedings of the National Academy of Sciences of the United States of America 96 27994151
2014 Decreased anxiety-like behavior and Gαq/11-dependent responses in the amygdala of mice lacking TRPC4 channels. The Journal of neuroscience : the official journal of the Society for Neuroscience 92 24599464
2015 Englerin A Agonizes the TRPC4/C5 Cation Channels to Inhibit Tumor Cell Line Proliferation. PloS one 91 26098886
2015 A background Ca2+ entry pathway mediated by TRPC1/TRPC4 is critical for development of pathological cardiac remodelling. European heart journal 89 26069213
2018 Electron cryo-microscopy structure of the canonical TRPC4 ion channel. eLife 86 29717981
2004 ATP-induced mitogenesis is mediated by cyclic AMP response element-binding protein-enhanced TRPC4 expression and activity in human pulmonary artery smooth muscle cells. American journal of physiology. Cell physiology 86 15229105
2012 Selective Gαi subunits as novel direct activators of transient receptor potential canonical (TRPC)4 and TRPC5 channels. The Journal of biological chemistry 85 22457348
2001 Functional differences between TRPC4 splice variants. The Journal of biological chemistry 85 11713258
2002 TRPC4 currents have properties similar to the pacemaker current in interstitial cells of Cajal. American journal of physiology. Cell physiology 80 12388058
2005 Activation of the endothelial store-operated ISOC Ca2+ channel requires interaction of protein 4.1 with TRPC4. Circulation research 78 16254212
2002 The role of endogenous human Trp4 in regulating carbachol-induced calcium oscillations in HEK-293 cells. The Journal of biological chemistry 78 11830588
2007 TRPC4 in rat dorsal root ganglion neurons is increased after nerve injury and is necessary for neurite outgrowth. The Journal of biological chemistry 72 17928298
2005 TRPC4 knockdown suppresses epidermal growth factor-induced store-operated channel activation and growth in human corneal epithelial cells. The Journal of biological chemistry 70 16033767
2002 TRPC4 can be activated by G-protein-coupled receptors and provides sufficient Ca(2+) to trigger exocytosis in neuroendocrine cells. The Journal of biological chemistry 69 11856742
2018 Ca2+ handling remodeling and STIM1L/Orai1/TRPC1/TRPC4 upregulation in monocrotaline-induced right ventricular hypertrophy. Journal of molecular and cellular cardiology 65 29634917
2005 Receptor-operated cation channels formed by TRPC4 and TRPC5. Naunyn-Schmiedeberg's archives of pharmacology 65 15902430
2009 Regulation of TRPC1 and TRPC4 cation channels requires an alpha1-syntrophin-dependent complex in skeletal mouse myotubes. The Journal of biological chemistry 64 19812031
2001 The transient receptor potential, TRP4, cation channel is a novel member of the family of calmodulin binding proteins. The Biochemical journal 64 11311128
2001 Alternative splice variants of hTrp4 differentially interact with the C-terminal portion of the inositol 1,4,5-trisphosphate receptors. FEBS letters 63 11163362
2004 TRPC4 forms store-operated Ca2+ channels in mouse mesangial cells. American journal of physiology. Cell physiology 62 15044151
2016 Critical roles of Gi/o proteins and phospholipase C-δ1 in the activation of receptor-operated TRPC4 channels. Proceedings of the National Academy of Sciences of the United States of America 61 26755577
2009 Interaction between TRPC1/TRPC4 assembly and STIM1 contributes to store-operated Ca2+ entry in mesangial cells. Experimental biology and medicine (Maywood, N.J.) 59 19307462
2020 Structural basis of TRPC4 regulation by calmodulin and pharmacological agents. eLife 58 33236980
1989 Interpathway regulation of the TRP4 gene of yeast. The EMBO journal 56 2656261
2015 Acute Treatment with a Novel TRPC4/C5 Channel Inhibitor Produces Antidepressant and Anxiolytic-Like Effects in Mice. PloS one 51 26317356
2005 Canonical transient receptor potential channel 4 (TRPC4) co-localizes with the scaffolding protein ZO-1 in human fetal astrocytes in culture. Glia 50 15540229
2013 During post-natal human myogenesis, normal myotube size requires TRPC1- and TRPC4-mediated Ca²⁺ entry. Journal of cell science 47 23549783
2013 Kisspeptin activation of TRPC4 channels in female GnRH neurons requires PIP2 depletion and cSrc kinase activation. Endocrinology 47 23744639
2005 TRPC4 is an essential component of the nonselective cation channel activated by muscarinic stimulation in mouse visceral smooth muscle cells. Molecules and cells 46 16404161
2009 Cell-cell contact formation governs Ca2+ signaling by TRPC4 in the vascular endothelium: evidence for a regulatory TRPC4-beta-catenin interaction. The Journal of biological chemistry 45 19996314
2017 TRPC1 and TRPC4 channels functionally interact with STIM1L to promote myogenesis and maintain fast repetitive Ca2+ release in human myotubes. Biochimica et biophysica acta. Molecular cell research 44 28185894
2010 The phospholipid-binding protein SESTD1 is a novel regulator of the transient receptor potential channels TRPC4 and TRPC5. The Journal of biological chemistry 43 20164195
1986 The TRP4 gene of Saccharomyces cerevisiae: isolation and structural analysis. Nucleic acids research 43 2428012
2015 Identification and optimization of 2-aminobenzimidazole derivatives as novel inhibitors of TRPC4 and TRPC5 channels. British journal of pharmacology 42 25816897
2014 TRPC4- and TRPC4-containing channels. Handbook of experimental pharmacology 39 24756704
2013 Conserved gating elements in TRPC4 and TRPC5 channels. The Journal of biological chemistry 39 23677990
2012 Effect of non-steroidal anti-inflammatory drugs and new fenamate analogues on TRPC4 and TRPC5 channels. Biochemical pharmacology 38 22285229
2014 A rat knockout model implicates TRPC4 in visceral pain sensation. Neuroscience 36 24388923
2012 The roles of G proteins in the activation of TRPC4 and TRPC5 transient receptor potential channels. Channels (Austin, Tex.) 35 22878724
2019 TRPC1 as a negative regulator for TRPC4 and TRPC5 channels. Pflugers Archiv : European journal of physiology 33 31222490
2018 Emerging Roles of Diacylglycerol-Sensitive TRPC4/5 Channels. Cells 33 30463370
2017 Na+ entry through heteromeric TRPC4/C1 channels mediates (-)Englerin A-induced cytotoxicity in synovial sarcoma cells. Scientific reports 33 29209034
2015 Regulation of neuropathic pain behavior by amygdaloid TRPC4/C5 channels. Neuroscience letters 33 26432495
2023 The Molecular Heterogeneity of Store-Operated Ca2+ Entry in Vascular Endothelial Cells: The Different roles of Orai1 and TRPC1/TRPC4 Channels in the Transition from Ca2+-Selective to Non-Selective Cation Currents. International journal of molecular sciences 32 36834672
2008 The specific activation of TRPC4 by Gi protein subtype. Biochemical and biophysical research communications 31 18854172
2006 Evidence that TRPC4 supports the calcium selective I(CRAC)-like current in human gingival keratinocytes. Pflugers Archiv : European journal of physiology 30 17031666
2007 Distribution of TRPC4 in developing and adult murine brain. Cell and tissue research 29 17345099
2004 Expression of TRPC4 channel protein that interacts with NHERF-2 in rat descending vasa recta. American journal of physiology. Cell physiology 29 15590898
2003 A novel N-terminal cyclic dynorphin A analogue cyclo(N,5)[Trp(3),Trp(4),Glu(5)] dynorphin A-(1-11)NH(2) that lacks the basic N-terminus. Journal of medicinal chemistry 29 12672226
2020 Sensory Neuron-Expressed TRPC4 Is a Target for the Relief of Psoriasiform Itch and Skin Inflammation in Mice. The Journal of investigative dermatology 27 32289348
2018 TRPC4/TRPC5 channels mediate adverse reaction to the cancer cell cytotoxic agent (-)-Englerin A. Oncotarget 27 30038709
2007 The first ankyrin-like repeat is the minimum indispensable key structure for functional assembly of homo- and heteromeric TRPC4/TRPC5 channels. Cell calcium 27 17624425
2007 Association of VASP with TRPC4 in PKG-mediated inhibition of the store-operated calcium response in mesangial cells. American journal of physiology. Renal physiology 27 17913834
2011 A gain-of-function SNP in TRPC4 cation channel protects against myocardial infarction. Cardiovascular research 26 21427121
2014 Novel role for TRPC4 in regulation of macroautophagy by a small molecule in vascular endothelial cells. Biochimica et biophysica acta 23 25476892
2019 Differential PI(4,5)P2 sensitivities of TRPC4, C5 homomeric and TRPC1/4, C1/5 heteromeric channels. Scientific reports 22 30755645
2013 Crucial role of TRPC1 and TRPC4 in cystitis-induced neuronal sprouting and bladder overactivity. PloS one 22 23922735
1990 Three GCN4 responsive elements act synergistically as upstream and as TATA-like elements in the yeast TRP4 promoter. The EMBO journal 22 1697266
2013 Differential regulation of TRPC4 in the vasopressin magnocellular system by water deprivation and hepatic cirrhosis in the rat. American journal of physiology. Regulatory, integrative and comparative physiology 20 24352411
2018 Gαi-mediated TRPC4 activation by polycystin-1 contributes to endothelial function via STAT1 activation. Scientific reports 19 29472562
2010 Association study of TRPC4 as a candidate gene for generalized epilepsy with photosensitivity. Neuromolecular medicine 18 20574736
2002 Replacement of the yeast TRP4 3' untranslated region by a hammerhead ribozyme results in a stable and efficiently exported mRNA that lacks a poly(A) tail. RNA (New York, N.Y.) 18 12003493
2020 Involvement of TRPC4 and 5 Channels in Persistent Firing in Hippocampal CA1 Pyramidal Cells. Cells 17 32033274
2016 Muscarinic Receptor Induced Contractions of the Detrusor are Mediated by Activation of TRPC4 Channels. The Journal of urology 17 27287524
2014 Dual depolarization responses generated within the same lateral septal neurons by TRPC4-containing channels. Pflugers Archiv : European journal of physiology 17 24121765
2001 Functional interaction between TRP4 and CFTR in mouse aorta endothelial cells. BMC physiology 17 11356184
1986 Synthesis and biological activity of analogs of dynorphin-A(1-13) substituted in positions 2 and 4: design of [Ala2,Trp4]-Dyn-A(1-13) as a putative selective opioid antagonist. Canadian journal of physiology and pharmacology 17 2875777
2008 Cyclic stretch decreases TRPC4 protein and capacitative calcium entry in rat vascular smooth muscle cells. Life sciences 16 18538797
1992 Sequence-specific initiator elements focus initiation of transcription to distinct sites in the yeast TRP4 promoter. The EMBO journal 16 1425591
2022 Inhibition of TRPC4 channel activity in colonic myocytes by tricyclic antidepressants disrupts colonic motility causing constipation. Journal of cellular and molecular medicine 15 35560982
2014 Identification of a membrane-targeting domain of the transient receptor potential canonical (TRPC)4 channel unrelated to its formation of a tetrameric structure. The Journal of biological chemistry 15 25349210
2008 The self-association of two N-terminal interaction domains plays an important role in the tetramerization of TRPC4. Cell calcium 15 19070363
2022 Magnolol and honokiol target TRPC4 to regulate extracellular calcium influx and relax intestinal smooth muscle. Journal of ethnopharmacology 14 35157953
2002 Cloning and functional expression of a novel splice variant of rat TRPC4. Circulation journal : official journal of the Japanese Circulation Society 14 12381092
2023 Molecular mechanisms of cholinergic neurotransmission in visceral smooth muscles with a focus on receptor-operated TRPC4 channel and impairment of gastrointestinal motility by general anaesthetics and anxiolytics. Neuropharmacology 13 37913983
2016 Calcium permeability of transient receptor potential canonical (TRPC) 4 channels measured by TRPC4-GCaMP6s. The Korean journal of physiology & pharmacology : official journal of the Korean Physiological Society and the Korean Society of Pharmacology 13 28066150
2015 Close spatio-association of the transient receptor potential canonical 4 (TRPC4) channel with Gαi in TRPC4 activation process. American journal of physiology. Cell physiology 13 25788576
2022 TRPC4 and GIRK channels underlie neuronal coding of firing patterns that reflect Gq/11-Gi/o coincidence signals of variable strengths. Proceedings of the National Academy of Sciences of the United States of America 12 35544691
2015 Intracellular spermine blocks TRPC4 channel via electrostatic interaction with C-terminal negative amino acids. Pflugers Archiv : European journal of physiology 12 26631167
2007 Ionic channels formed by TRPC4. Handbook of experimental pharmacology 12 17217052
2024 TRPC4 aggravates hypoxic pulmonary hypertension by promoting pulmonary endothelial cell apoptosis. Free radical biology & medicine 11 38636714

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