Affinage

TRPV4

Transient receptor potential cation channel subfamily V member 4 · UniProt Q9HBA0

Length
871 aa
Mass
98.3 kDa
Annotated
2026-06-10
100 papers in source corpus 31 papers cited in narrative 31 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TRPV4 is a polymodal, Ca2+-permeable non-selective cation channel that transduces osmotic, mechanical, thermal, and chemical stimuli into Ca2+-dependent cellular responses governing cytoskeletal remodeling, vascular tone, mechanosensing, immune activation, and sensory signaling (PMID:11094154, PMID:11827975, PMID:33888579). The channel is directly gated by hypotonic cell swelling, producing a swelling-activated cation current with an Eisenman-IV permeability sequence distinct from volume-regulated anion channels (PMID:11713648, PMID:11094154), and by the synthetic agonist 4α-PDD, which binds the base of the S1-S4 voltage-sensing-like domain (VSLD) to open the pore independently of PKC (PMID:11827975, PMID:37353478); antagonists such as HC-067047 bind the same VSLD and stabilize closed states via a π-to-α transition in the pore helix S6 and a fourfold-to-twofold symmetry change (PMID:37353478, PMID:38659239). Pore residues Asp672, Asp682, and Met680 set Ca2+ permeability, outward rectification, and Ruthenium Red sensitivity (PMID:12093812). The cytosolic N-terminal ankyrin repeat domain physically binds RhoA, an interaction that mutually suppresses channel activity and RhoA activation to promote neurite extension; neuropathy-associated mutations disrupt this interface, and cryo-EM places RhoA on the membrane-facing surface of the ankyrin repeats (PMID:33664271, PMID:37353478). Downstream of Ca2+ influx, TRPV4 drives cytoskeletal and migratory programs through RhoA/ROCK1/LIMK/cofilin (PMID:33230171), Cdc42/N-WASP (PMID:32843668), and AKT/Rac1 (PMID:29928875), and contributes to mechanosensing and matrix-stiffness signaling via YAP (PMID:37702061, PMID:35182379). TRPV4 forms functional complexes with eNOS to promote vasodilation and regulate blood pressure (PMID:34822720) and couples to the scramblase TMEM16F within Ca2+ microdomains to drive cell fusion (PMID:35670667). In immune and glial cells it mediates crystal-induced NLRP3 inflammasome activation and IL-1β release in macrophages (PMID:34663597), CaSR-coupled M1 polarization (PMID:36606511), and microglial activation and motility (PMID:33888579, PMID:36701202), and in sensory neurons it mediates serotonin-evoked itch (PMID:26763435, PMID:36049541). Channel surface density and gating are tuned by Ca2+/PI3K/PKC/RhoA-dependent endosomal trafficking (PMID:30728775), membrane cholesterol content (PMID:34710431), and transcriptional repression by the progesterone receptor (PMID:19701771).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2000 Medium

    Established that the murine TRPV4 ortholog is itself an osmosensitive Ca2+-permeable channel, defining its founding function as an osmosensor rather than an accessory subunit.

    Evidence Heterologous expression with cytosolic Ca2+ measurement under hypoosmotic challenge

    PMID:11094154

    Open questions at the time
    • Single readout system did not resolve direct vs. indirect osmotic gating
    • No biophysical pore characterization
  2. 2001 High

    Defined the biophysical signature of swelling-activated TRPV4 current and distinguished it from the endogenous volume-regulated anion channel, clarifying channel identity.

    Evidence Whole-cell patch-clamp with ionic substitution and ionic-strength/GTPγS controls in HEK-293

    PMID:11713648

    Open questions at the time
    • Mechanism linking swelling to gating not resolved
    • Did not identify pore residues
  3. 2002 High

    Identified a direct small-molecule agonist (4α-PDD) and the pore residues governing ion selectivity, converting TRPV4 into a pharmacologically and structurally tractable channel.

    Evidence Patch-clamp + Ca2+ imaging with PKC dissection (4α-PDD); site-directed mutagenesis of pore residues with reversal-potential measurements

    PMID:11827975 PMID:12093812

    Open questions at the time
    • Agonist binding site not localized at atomic resolution in these studies
    • Physiological agonist remained undefined
  4. 2009 High

    Showed that TRPV4 abundance is transcriptionally controlled by the progesterone receptor, establishing hormonal regulation of channel expression.

    Evidence RT-PCR, Western blot, patch-clamp, Ca2+ imaging, siRNA, promoter-luciferase reporter in epithelial cells

    PMID:19701771

    Open questions at the time
    • Direct vs. indirect promoter binding not resolved
    • Physiological contexts of PR-TRPV4 regulation limited
  5. 2016 High

    Connected TRPV4 to cytoskeletal mechanics and cancer cell invasion, showing channel activity reshapes the actin cortex and enables transendothelial migration and serotonin-evoked itch in distinct tissues.

    Evidence siRNA/overexpression with AFM stiffness measurement and xenografts (breast cancer); TRPV4 KO behavioral and DRG Ca2+ imaging (itch)

    PMID:26763435 PMID:27291497

    Open questions at the time
    • Molecular link between channel and cortex remodeling not fully defined
    • Itch transduction pathway upstream of TRPV4 unresolved at this stage
  6. 2018 Medium

    Mapped TRPV4 onto specific migratory and mechanotransduction effector pathways (AKT/Rac1; osteoblast RANKL/NFATc1), defining downstream signaling outputs.

    Evidence Pharmacological gain/loss-of-function with phospho-signaling Western blots (glioma); siRNA/shRNA and Ca2+ imaging in osteoblasts

    PMID:29928875 PMID:30328352

    Open questions at the time
    • Direct vs. indirect coupling to AKT not established
    • Contribution of co-acting channels (TRPM3) not fully separated
  7. 2019 Medium

    Revealed TRPV4 surface density is dynamically regulated by Ca2+/PI3K/PKC/RhoA-dependent endosomal trafficking, and that TRPV4 can form heteromeric complexes with TRPV1.

    Evidence Single-molecule trafficking imaging with pathway inhibitors; proximity ligation assay and patch-clamp for TRPV1/TRPV4 heteromers

    PMID:30728775 PMID:31369032

    Open questions at the time
    • Stoichiometry of heteromers undefined
    • Trafficking determinants on TRPV4 not mapped
  8. 2021 High

    Identified the TRPV4 N-terminal ankyrin domain as a direct RhoA-binding interface that reciprocally controls channel activity and cytoskeletal outgrowth, providing a molecular basis for TRPV4 neuropathy.

    Evidence Unbiased interaction screen, reciprocal Co-IP, channel recordings, disease-mutant neurite assays, Drosophila rescue

    PMID:33664271

    Open questions at the time
    • Structural details of the interface not yet resolved in this study
    • Skeletal dysplasia mutations act through a distinct mechanism left undefined
  9. 2021 High

    Expanded TRPV4 into immune, glial, microdomain, and lipid-signaling roles, showing it drives crystal-induced NLRP3/IL-1β in macrophages, couples to TMEM16F for cell fusion, mediates thermosensitive microglial motility, and requires PLA2/CYP450/EET intermediates in microglia.

    Evidence TRPV4 KO + patch-clamp + in vivo gout models; Ca2+-microdomain electrophysiology and fusion assays; KO two-photon imaging; pharmacological PLA2/CYP450 pathway dissection

    PMID:33624376 PMID:33888579 PMID:34663597 PMID:35670667

    Open questions at the time
    • Physical proximity of TRPV4 to TMEM16F not structurally resolved
    • Mechanism linking crystal sensing to TRPV4 gating undefined
    • Source/identity of endogenous EET ligand in vivo unclear
  10. 2022 Medium

    Defined receptor-coupled and transcriptional effector arms of TRPV4 signaling, including CaSR coupling for M1 polarization, 5-HTR2B/PKC phosphorylation in itch, and YAP/STAT3-driven neuroinflammation.

    Evidence KO macrophages + pharmacology + ELISA (CaSR); KO/antagonist + DRG Ca2+ imaging + PKC inhibitor (itch); siRNA of TRPV4/YAP + seizure model (astrocytes)

    PMID:35182379 PMID:36049541 PMID:36606511

    Open questions at the time
    • Direct PKC phosphorylation sites on TRPV4 not biochemically mapped
    • Sequence of YAP activation relative to channel gating unresolved
  11. 2023 High

    Provided atomic-resolution mechanism: cryo-EM placed RhoA on the ankyrin-domain surface and localized agonist/antagonist action at the VSLD with defined gating transitions, while establishing the TRPV4-eNOS vasodilatory complex and endothelial mechanotransduction roles.

    Evidence Cryo-EM of TRPV4-RhoA and ligand-bound states; Co-IP/FRET/mutagenesis + endothelial KO (eNOS); endothelium-specific KO + RNA-seq + stiffness gels (cardiac hypertrophy)

    PMID:34822720 PMID:37353478 PMID:37702061

    Open questions at the time
    • Structural basis of mechanical/osmotic gating not captured
    • eNOS-binding interface residues require independent validation
  12. 2024 High

    Refined the VSLD pharmacophore by resolving two antagonist binding modes and an associated symmetry transition, informing inhibitor design.

    Evidence Cryo-EM of two antagonist complexes with electrophysiology and MD simulation

    PMID:38659239

    Open questions at the time
    • Functional relevance of symmetry transition in native cells untested
    • Selectivity over other TRPV channels not addressed

Open questions

Synthesis pass · forward-looking unresolved questions
  • The structural basis by which physical stimuli (osmotic swelling, heat, mechanical strain) are transduced into pore opening remains unresolved despite multiple ligand-bound structures.
  • No structure of a mechanically/osmotically gated state
  • Role of membrane lipids and cytoskeleton in physiological gating not structurally defined
  • Mechanism distinguishing TRPV4 from PIEZO1 mechanotransduction unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 3 GO:0060089 molecular transducer activity 3 GO:0140299 molecular sensor activity 3 GO:0008092 cytoskeletal protein binding 2
Localization
GO:0005856 cytoskeleton 2 GO:0005886 plasma membrane 2 GO:0005768 endosome 1
Pathway
R-HSA-112316 Neuronal System 3 R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 3 R-HSA-382551 Transport of small molecules 2
Partners
CAV1NOS3RHOATMEM16FTRPV1
Complex memberships
TRPV1-TRPV4 heteromeric channelTRPV4-RhoA complexTRPV4-eNOS complex

Evidence

Reading pass · 31 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 4α-Phorbol 12,13-didecanoate (4α-PDD) directly gates TRPV4 as an agonist, activating an outwardly rectifying, Ca2+-permeable cation channel (PCa/PNa ≈ 5.8) in cells expressing hVRL-2/mTRP12; this activation is independent of protein kinase C and is modulated by intracellular Ca2+ (inhibitory IC50 ≈ 406 nM). Ruthenium Red blocks inward currents in a voltage-dependent manner. Whole-cell patch-clamp and Ca2+ imaging in stably/transiently transfected 1321N1 and HEK-293 cells; pharmacological PKC dissection; native aortic endothelial cells The Journal of biological chemistry High 11827975
2002 Asp672 and Asp682 in the pore region are critical determinants of Ca2+ permeability and outward rectification; Met680 at the putative selectivity filter is essential for current amplitude and Ca2+ permeation; Asp682 (but not Asp672) controls Ruthenium Red affinity; Lys675 (the only positive pore residue) is dispensable for pore function. Site-directed mutagenesis combined with whole-cell patch-clamp and ion substitution reversal-potential measurements in transfected HEK-293 cells The Journal of biological chemistry High 12093812
2000 Trp12 (murine TRPV4 ortholog) forms a Ca2+-permeable channel: heterologous expression elevates basal cytosolic Ca2+ and confers a further increase upon hypoosmotic stimulation, establishing osmosensory gating of this channel. Heterologous expression in transfected cells with cytosolic Ca2+ measurements under hypoosmotic challenge FEBS letters Medium 11094154
2001 Heterologous expression of TRP12/OTRPC4 (TRPV4) in HEK-293 cells produces a swelling-activated cation current with Eisenman-IV permeability sequence (PK>PCs>PNa>PLi); overexpression simultaneously down-regulates the endogenous volume-regulated anion channel (VRAC). Unlike VRAC, TRP12 is not activated by reduced intracellular ionic strength or intracellular GTPγS at constant volume. Whole-cell patch-clamp in transfected HEK-293 cells with hypotonic swelling; ionic substitution; pharmacological and ionic-strength manipulations Pflugers Archiv : European journal of physiology High 11713648
2021 TRPV4 physically interacts with RhoA via the TRPV4 N-terminal ankyrin repeat domain; this interaction suppresses TRPV4 channel activity and inhibits RhoA activation, thereby promoting neurite extension. Neuropathy-causing (but not skeletal dysplasia) mutations in the N-terminal domain disrupt TRPV4-RhoA binding, impairing cytoskeletal outgrowth. RhoA inhibition rescues neurite length both in vitro and in a Drosophila model of TRPV4 neuropathy. Unbiased protein interaction screen, Co-IP, functional channel recordings, neurite-outgrowth assays with disease-associated point mutants, Drosophila in vivo rescue Nature communications High 33664271
2023 Cryo-EM structure of human TRPV4 in complex with GTPase RhoA shows RhoA contacts the membrane-facing surface of the TRPV4 ankyrin repeat domains. The agonist 4α-PDD and inhibitor HC-067047 bind at the base of the S1-S4 bundle (voltage-sensing-like domain): 4α-PDD binding leads to pore opening, whereas HC-067047 stabilizes a closed state involving a π-to-α helix transition in pore-forming helix S6. Cryo-EM structure determination with functional validation; binding-site mutagenesis context inferred from disease-mutation mapping at the RhoA interface Nature communications High 37353478
2024 Cryo-EM structures of human TRPV4 with two potent antagonists reveal both ligands bind the voltage-sensing-like domain (VSLD) and stabilize closed channel states; one antagonist occupies the canonical VSLD pocket and the other a novel extended VSLD pocket. Antagonist binding induces a fourfold-to-twofold symmetry transition in the channel. Cryo-EM structure determination complemented with functional electrophysiology and molecular dynamics simulation Advanced science High 38659239
2019 TRPV4 stimulation with GSK1016790A decreases plasma-membrane TRPV4 density within ~20 min through translocation to recycling endosomes via two modes of vesicular fusion; surface density is regulated by intracellular Ca2+ release and controlled by a PI3K/PKC/RhoA signaling pathway. Single-molecule imaging, live-cell fluorescence, pharmacological inhibition of PI3K, PKC, RhoA in transfected cells Frontiers in pharmacology Medium 30728775
2009 Progesterone, acting through the progesterone receptor (PR), transcriptionally represses TRPV4 expression; PR activation reduces TRPV4 mRNA, protein, and 4α-PDD-evoked currents/Ca2+ signals in airway and mammary epithelial cells. The effect is reversed by the PR antagonist RU-486 or siRNA knockdown of both PRA and PRB isoforms. PR co-expression suppresses TRPV4 promoter-driven reporter activity. RT-PCR, Western blot, whole-cell patch-clamp, Ca2+ imaging, siRNA knockdown, promoter-luciferase reporter assays Pflugers Archiv : European journal of physiology High 19701771
2021 TRPV4-mediated Ca2+ influx functionally couples to the Ca2+-activated phospholipid scramblase TMEM16F within Ca2+ microdomains in human trophoblasts, driving TMEM16F activation and subsequent trophoblast syncytialization. Pharmacological inhibition or gene silencing of TRPV4 reduces TMEM16F activation and cell fusion. Patch-clamp electrophysiology, pharmacological agonist/antagonist, siRNA knockdown, cell fusion assays in human trophoblast cell line eLife High 35670667
2021 Depolarized mitochondria switch TRPV4-evoked Ca2+ signaling from IP3R-dependent Ca2+-induced Ca2+ release to mitochondria-independent Ca2+ waves mediated by ATP release through pannexin channels, which then activate purinergic receptors to trigger IP3 store release. This identifies mitochondria as regulators of TRPV4-Ca2+ signal mode in endothelial cells. Ca2+ imaging (Cal520) in rat mesenteric artery endothelium; pharmacological dissection with CCCP, rotenone, oligomycin, HC067047, U73122, caffeine, suramin, apyrase, probenecid British journal of pharmacology Medium 34605007
2023 Microglial TRPV4 mediates microglial activation and proliferation after nerve injury, and promotes excitatory spinal neuron plasticity through release of lipocalin-2, linking peripheral nerve injury to central sensitization and neuropathic pain. Genetic ablation (Trpv4 KO) and pharmacological blockade in spared nerve injury mouse model; lipocalin-2 measurement; electrophysiological and morphological assessment of spinal neurons The Journal of clinical investigation Medium 36701202
2021 TRPV4 mediates NLRP3 inflammasome activation induced by crystalline (but not non-crystalline) NLRP3 activators in synovial macrophages, driving IL-1β production and crystal-induced gouty arthritis; TRPV4 expression is functionally confirmed in synovial macrophages and upregulated by MSU crystal stimulation. Whole-cell patch-clamp, live-cell Ca2+ imaging, TRPV4 KO and pharmacological inhibition, in vitro NLRP3 inflammasome assays, in vivo gout models Annals of the rheumatic diseases High 34663597
2020 TRPV4 activates the Cdc42/N-WASP pathway to regulate formation of invadopodia and filopodia at cellular protrusions, promoting glioblastoma cell migration and invasion in vitro and tumor growth in vivo. TRPV4 co-localizes and interacts with F-actin at protrusions. Co-IP/co-localization with F-actin, TRPV4 siRNA knockdown, pharmacological agonist/antagonist, invasion assays, subcutaneous and intracranial mouse xenograft models Scientific reports Medium 32843668
2018 TRPV4 activation promotes glioma cell migration and invasion via AKT phosphorylation leading to Rac1 activation; pharmacological TRPV4 agonism enhances and antagonism suppresses this pathway. Pharmacological agonist (GSK1016790A) and antagonist (HC-067047), Western blot for AKT phosphorylation and Rac1 activation, migration/invasion assays Biochemical and biophysical research communications Medium 29928875
2016 TRPV4 is required for breast cancer cell invasion and transendothelial migration (but not proliferation); TRPV4 overexpression promotes cell softness, blebbing, and actin cortex reorganization, reducing cell rigidity. siRNA knockdown, overexpression, transendothelial migration assays, mouse xenograft, atomic force microscopy/cell stiffness measurements, live imaging Scientific reports Medium 27291497
2020 TRPV4 calcium influx activates the RhoA/ROCK1 pathway leading to LIMK/cofilin activation, which regulates F-actin and paxillin (PXN) levels, driving endometrial cancer cell migration and invasion. Proteomic/bioinformatics analysis, overexpression and knockdown, pharmacological Ca2+ manipulation, Western blot for RhoA/ROCK1/LIMK/cofilin/paxillin, migration assays, in vivo xenograft Cell death & disease Medium 33230171
2022 TRPV4 activity in astrocytes promotes neuroinflammation through a TRPV4/Ca2+/YAP/STAT3 signaling pathway; YAP siRNA knockdown blocks 4-AP-induced astrocyte reactivity and cytokine release downstream of TRPV4. siRNA knockdown of TRPV4 and YAP, pharmacological TRPV4 inhibition, Ca2+ imaging, cytokine ELISA, in vivo mouse seizure model and human epileptic tissue analysis Neurotherapeutics Medium 35182379
2022 Calcium-sensing receptor (CaSR) couples to TRPV4 channels in macrophages via PLA2/cytochrome P450 and PLC/PKC pathways; CaSR activation drives extracellular Ca2+ entry predominantly through TRPV4, and this CaSR-TRPV4 coupling promotes M1 macrophage polarization and cytokine (IL-1β, TNFα) production. Pharmacological inhibition of CaSR and TRPV4, TRPV4 KO mice peritoneal macrophages, digital Ca2+ imaging, immunofluorescence, ELISA, Western blot, qPCR Acta physiologica Medium 36606511
2023 Endothelial TRPV4 forms a functional complex with eNOS (endothelial nitric oxide synthase); TRPV4-eNOS interaction promotes vasodilation and regulates blood pressure. This interaction is impaired during hypertension, and a small molecule (JNc-463) designed to enhance TRPV4-eNOS interaction restores vasodilation and exerts antihypertensive effects in mice. Co-immunoprecipitation, immuno-FRET, site-directed mutagenesis to map binding site, endothelium-specific TRPV4 KO mice, single-cell RNA-seq, molecular docking and in vivo pharmacology British journal of pharmacology High 34822720
2021 Retinal microglial TRPV4 activation (by agonist GSK1016790A or hypotonicity) requires intermediary activation of phospholipase A2 (PLA2), cytochrome P450, and epoxyeicosatrienoic acid (EET) production; TRPV4 activation in microglia triggers Ca2+ elevation, outwardly rectifying cation current, and retraction of higher-order processes. Ca2+ imaging, whole-cell patch-clamp, pharmacological inhibition of PLA2/CYP450/EET pathway and TRPV4 antagonist HC067047 in dissociated and intact microglia Glia Medium 33624376
2021 Thermosensitive TRPV4 channels mediate temperature-dependent microglial movement within the physiological body temperature range (>34°C activation threshold in brain); TRPV4 deletion abolishes temperature-dependent microglial motility both in vitro and in vivo. TRPV4 KO mice, live two-photon imaging of microglia in vivo, in vitro motility assays across temperature range, pharmacological TRPV4 inhibition Proceedings of the National Academy of Sciences of the United States of America High 33888579
2016 TRPV4 mediates serotonin (5-HT)-evoked itch: TRPV4 KO mice show significantly fewer 5-HT-induced (but not histamine- or SLIGRL-induced) scratching bouts; ~90% of 5-HT-sensitive DRG neurons are TRPV4-immunoreactive; TRPV4 antagonism suppresses 5-HT-evoked Ca2+ responses in DRG neurons. TRPV4 KO mice behavioral assay, pharmacological antagonist in vivo, Ca2+ imaging in primary DRG neurons, immunostaining The Journal of investigative dermatology High 26763435
2018 Hypo-osmotic stress increases RANKL and NFATc1 expression in osteoblasts via Ca2+ influx through both TRPM3 and TRPV4; genetic knockdown of Trpv4 (and Trpm3) reduces hypotonic-stress-induced Ca2+ rise and RANKL/NFATc1 expression. Pharmacological agonists/antagonists of TRPM3 and TRPV4, siRNA/shRNA knockdown, Ca2+ imaging, Western blot in primary mouse osteoblasts and MC3T3-E1 cells Journal of molecular endocrinology Medium 30328352
2021 Membrane cholesterol depletion (with MβCD) augments TRPV4 activation by agonist, osmotic swelling, and mechanical strain, and increases plasma-membrane TRPV4 expression. TRPV4 channels reside primarily outside cholesterol-enriched caveolin/lipid-raft domains; cholesterol repletion reverses these effects. MβCD induces TRPV4-dependent currents in Xenopus oocytes. MβCD cholesterol depletion/repletion, GSK1016790A activation assays, co-immunoprecipitation with caveolin-1, electrophysiology in Xenopus oocytes, confocal imaging in trabecular meshwork cells Journal of lipid research Medium 34710431
2019 TRPV1 and TRPV4 form functional heteromeric channel complexes in retinal microvascular endothelial cells (RMECs), as demonstrated by proximity ligation assay and patch-clamp recording. Inhibition of either channel suppresses in vitro tubulogenesis and reduces retinal neovascularization in vivo in the OIR mouse model. Proximity ligation assay, patch-clamp electrophysiology, pharmacological inhibition, in vivo OIR mouse model, in vitro angiogenesis assays Investigative ophthalmology & visual science Medium 31369032
2022 miR-203b-3p activates the 5-HTR2B receptor, leading to PKC-dependent phosphorylation of TRPV4, which triggers itch in sensory neurons and mouse scratch behavior. Genetic deletion or pharmacological antagonism of TRPV4 attenuates this itch response. TRPV4 KO mice, pharmacological antagonism (HC067047), PKC inhibitor, Ca2+ imaging in DRG neurons, behavioral scratch assays, computer simulation of miRNA-receptor interaction The Journal of investigative dermatology Medium 36049541
2022 TRPV4 activation induces exocytosis in melanoma cells through interactions with ER folding and vesicle trafficking proteins triggered by Ca2+ entry; this is followed by mitochondrial crista morphology changes leading to ferroptosis. TRPV4-specific agonists, co-IP to identify folding/vesicle trafficking protein interactions, live-cell vesicle imaging, mitochondrial morphology analysis in melanoma A375 cells International journal of molecular sciences Low 35456964
2023 Endothelial-specific TRPV4 knockout protects against pressure-overload cardiac hypertrophy by enhancing coronary angiogenesis; mechanistically, TRPV4 downregulation activates matrix stiffness-dependent YAP and VEGFR2 via the Rho/ROCK/LATS kinase pathway, upregulating proangiogenic factors (VEGFα, NOS3, FGF2). Endothelium-specific TRPV4 KO mice (transverse aortic constriction model), RNA-seq, siRNA, Western blot, qPCR, confocal immunofluorescence, extracellular matrix gels of varying stiffness Hypertension Medium 37702061
2021 Substrate mechanics and cytoskeletal integrity modulate mechanically evoked TRPV4 currents, and TRPV4 mechanical activation is distinct from PIEZO1 activation in the same cell type; point mutations associated with TRPV4 phosphorylation and arthropathy alter mechanical (but not chemical) channel gating. Electrophysiology on substrates of varying stiffness, pharmacological cytoskeletal disruption, comparison of disease-associated point mutants for mechanical vs. chemical gating Frontiers in bioengineering and biotechnology Medium 33537292
2021 Pharmacological activation of TRPV4 increases canonical TGFβ signaling in chondrocytes in a Ca2+/CamKII-dependent manner; this potentiation only occurs when TRPV4 is activated after (not before) TGFβ stimulation. RNA-seq identifies JUN and SP1 as key transcription factors mediating this crosstalk. Pharmacological TRPV4 activation/inhibition, CamKII inhibitor, TRPV4 knockdown, TGFβ reporter assays, RNA-seq in chondrocytes Cells Medium 33805168

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Activation of TRPV4 channels (hVRL-2/mTRP12) by phorbol derivatives. The Journal of biological chemistry 485 11827975
2004 TRPV4 calcium entry channel: a paradigm for gating diversity. American journal of physiology. Cell physiology 373 14707014
2016 TRPV4: Molecular Conductor of a Diverse Orchestra. Physiological reviews 328 27252279
2002 Molecular determinants of permeation through the cation channel TRPV4. The Journal of biological chemistry 262 12093812
2000 Trp12, a novel Trp related protein from kidney. FEBS letters 248 11094154
2013 The puzzle of TRPV4 channelopathies. EMBO reports 246 23306656
2021 Cannabidiol inhibits human glioma by induction of lethal mitophagy through activating TRPV4. Autophagy 182 33629929
2001 Identification and characterization of a novel human vanilloid receptor-like protein, VRL-2. Physiological genomics 181 11160995
2013 TRPV4 and the regulation of vascular tone. Journal of cardiovascular pharmacology 142 23107877
2014 The TRPV4 channel. Handbook of experimental pharmacology 131 24756711
2003 The TRPV4 channel: structure-function relationship and promiscuous gating behaviour. Pflugers Archiv : European journal of physiology 125 12715179
2011 TRPV4 agonists and antagonists. Current topics in medicinal chemistry 118 21671873
2016 TRPV4 Regulates Breast Cancer Cell Extravasation, Stiffness and Actin Cortex. Scientific reports 111 27291497
2016 Involvement of TRPV4 in Serotonin-Evoked Scratching. The Journal of investigative dermatology 110 26763435
2001 Differential activation of the volume-sensitive cation channel TRP12 (OTRPC4) and volume-regulated anion currents in HEK-293 cells. Pflugers Archiv : European journal of physiology 110 11713648
2020 TRPV4-A Missing Link Between Mechanosensation and Immunity. Frontiers in immunology 100 32210976
2020 Calcium and TRPV4 promote metastasis by regulating cytoskeleton through the RhoA/ROCK1 pathway in endometrial cancer. Cell death & disease 100 33230171
2020 TRPV4: A Physio and Pathophysiologically Significant Ion Channel. International journal of molecular sciences 98 32481620
2023 A TRPV4-dependent neuroimmune axis in the spinal cord promotes neuropathic pain. The Journal of clinical investigation 85 36701202
2007 TRPV4. Handbook of experimental pharmacology 84 17217058
2019 The TRPV4 Agonist GSK1016790A Regulates the Membrane Expression of TRPV4 Channels. Frontiers in pharmacology 75 30728775
2014 TRPV4 as a therapeutic target for joint diseases. Naunyn-Schmiedeberg's archives of pharmacology 75 25519495
2019 Role of macrophage TRPV4 in inflammation. Laboratory investigation; a journal of technical methods and pathology 72 31645630
2012 TRPV4-associated skeletal dysplasias. American journal of medical genetics. Part C, Seminars in medical genetics 72 22791502
2021 Mechanosensitive TRPV4 is required for crystal-induced inflammation. Annals of the rheumatic diseases 71 34663597
2008 Molecular mechanisms of TRPV4-mediated neural signaling. Annals of the New York Academy of Sciences 71 19076362
2016 Modulation of TRPV4 by diverse mechanisms. The international journal of biochemistry & cell biology 69 27425399
2022 TRPV4 contributes to ER stress and inflammation: implications for Parkinson's disease. Journal of neuroinflammation 64 35093118
2014 TRPV4: physiological role and therapeutic potential in respiratory diseases. Naunyn-Schmiedeberg's archives of pharmacology 63 25342095
2020 Endothelial TRPV4 channels and vasodilator reactivity. Current topics in membranes 60 32402646
2023 Structure of human TRPV4 in complex with GTPase RhoA. Nature communications 57 37353478
2010 TRPV4-mediated channelopathies. Channels (Austin, Tex.) 57 20676052
2020 TRPV4 integrates matrix mechanosensing with Ca2+ signaling to regulate extracellular matrix remodeling. The FEBS journal 56 33300268
2014 TRPV4: new therapeutic target for inflammatory bowel diseases. Biochemical pharmacology 53 24440740
2021 Membrane cholesterol regulates TRPV4 function, cytoskeletal expression, and the cellular response to tension. Journal of lipid research 50 34710431
2022 TRPV4 and PIEZO Channels Mediate the Mechanosensing of Chondrocytes to the Biomechanical Microenvironment. Membranes 49 35207158
2009 The progesterone receptor regulates the expression of TRPV4 channel. Pflugers Archiv : European journal of physiology 48 19701771
2005 TRPV4 as osmosensor: a transgenic approach. Pflugers Archiv : European journal of physiology 48 15952033
2021 Neuropathy-causing TRPV4 mutations disrupt TRPV4-RhoA interactions and impair neurite extension. Nature communications 46 33664271
2005 TRPV4 and the mammalian kidney. Pflugers Archiv : European journal of physiology 46 15988590
2022 A novel antagonist of TRPM2 and TRPV4 channels: Carvacrol. Metabolic brain disease 45 34989943
2021 TRPV4 channels mediate the mechanoresponse in retinal microglia. Glia 44 33624376
2021 Thermosensitive TRPV4 channels mediate temperature-dependent microglia movement. Proceedings of the National Academy of Sciences of the United States of America 43 33888579
2010 TRPV4-pathy, a novel channelopathy affecting diverse systems. Journal of human genetics 43 20505684
2024 Electroacupuncture ameliorates neuroinflammation by inhibiting TRPV4 channel in ischemic stroke. CNS neuroscience & therapeutics 39 38334061
2020 The Role of TRPV4 in Regulating Innate Immune Cell Function in Lung Inflammation. Frontiers in immunology 39 32676078
2020 TRPV4 activates the Cdc42/N-wasp pathway to promote glioblastoma invasion by altering cellular protrusions. Scientific reports 39 32843668
2020 The role of TRPV4 channels in ocular function and pathologies. Experimental eye research 39 32979394
2012 Novel insights into TRPV4 function in the kidney. Pflugers Archiv : European journal of physiology 39 23207579
2020 TRPV4 activation by thermal and mechanical stimuli in disease progression. Laboratory investigation; a journal of technical methods and pathology 38 31896814
2018 TRPV4: a Sensor for Homeostasis and Pathological Events in the CNS. Molecular neurobiology 38 29582401
2017 The role of TRPV4 in fibrosis. Gene 38 29126921
2021 TRPV4 antagonists: a patent review (2015-2020). Expert opinion on therapeutic patents 37 33724130
2018 TRPV4 promotes the migration and invasion of glioma cells via AKT/Rac1 signaling. Biochemical and biophysical research communications 37 29928875
2022 Functional coupling between TRPV4 channel and TMEM16F modulates human trophoblast fusion. eLife 35 35670667
2019 Involvement of TRPV1 and TRPV4 Channels in Retinal Angiogenesis. Investigative ophthalmology & visual science 35 31369032
2022 Diverse Roles of TRPV4 in Macrophages: A Need for Unbiased Profiling. Frontiers in immunology 34 35126384
2021 Modulating the Mechanical Activation of TRPV4 at the Cell-Substrate Interface. Frontiers in bioengineering and biotechnology 34 33537292
2018 TRPM3/TRPV4 regulates Ca2+-mediated RANKL/NFATc1 expression in osteoblasts. Journal of molecular endocrinology 34 30328352
2022 TRPV4 Role in Neuropathic Pain Mechanisms in Rodents. Antioxidants (Basel, Switzerland) 33 36670886
2020 TRPV4 blockade suppresses atrial fibrillation in sterile pericarditis rats. JCI insight 33 33119551
2016 TRPV4 ion channel as important cell sensors. Journal of anesthesia 33 27506578
2022 Sensory Neuron-TRPV4 Modulates Temporomandibular Disorder Pain Via CGRP in Mice. The journal of pain 31 36509176
2012 TRPV4 axonal neuropathy spectrum disorder. Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia 31 22617546
2023 Mechanoregulatory role of TRPV4 in prenatal skeletal development. Science advances 29 36696489
2018 Mechanosensitive Ion Channels: TRPV4 and P2X7 in Disseminating Cancer Cells. Cancer journal (Sudbury, Mass.) 29 29601335
2024 The chondrocyte "mechanome": Activation of the mechanosensitive ion channels TRPV4 and PIEZO1 drives unique transcriptional signatures. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 28 38959010
2023 Deletion of Endothelial TRPV4 Protects Heart From Pressure Overload-Induced Hypertrophy. Hypertension (Dallas, Tex. : 1979) 28 37702061
2022 Endothelial TRPV4-eNOS coupling as a vital therapy target for treatment of hypertension. British journal of pharmacology 28 34822720
2022 TRPV4: A trigger of pathological RhoA activation in neurological disease. BioEssays : news and reviews in molecular, cellular and developmental biology 27 35297520
2021 Ca2+ Signaling by TRPV4 Channels in Respiratory Function and Disease. Cells 27 33917551
2020 Emerging roles of the TRPV4 channel in bladder physiology and dysfunction. The Journal of physiology 27 33052604
2021 TRPing on Cell Swelling - TRPV4 Senses It. Frontiers in immunology 26 34616399
2022 Glucosylsphingosine evokes pruritus via activation of 5-HT2A receptor and TRPV4 in sensory neurons. British journal of pharmacology 25 34766332
2022 Inhibition of Transient Receptor Potential Vanilloid 4 (TRPV4) Mitigates Seizures. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics 25 35182379
2017 Fluid-induced lung injury-role of TRPV4 channels. Pflugers Archiv : European journal of physiology 25 28456852
2016 Renoprotection: focus on TRPV1, TRPV4, TRPC6 and TRPM2. Acta physiologica (Oxford, England) 25 28028935
2023 Pathophysiological Roles of the TRPV4 Channel in the Heart. Cells 24 37371124
2023 TRPV4 regulates osteoblast differentiation and mitochondrial function that are relevant for channelopathy. Frontiers in cell and developmental biology 24 37377733
2021 Role of TRPV4 channel in vasodilation and neovascularization. Microcirculation (New York, N.Y. : 1994) 24 33971061
2020 Channels that Cooperate with TRPV4 in the Brain. Journal of molecular neuroscience : MN 24 32524421
2024 The Multifaceted Functions of TRPV4 and Calcium Oscillations in Tissue Repair. International journal of molecular sciences 23 38256251
2023 Astrocytic TRPV4 Channels and Their Role in Brain Ischemia. International journal of molecular sciences 23 37108263
2020 Modulating TRPV4 channels with paclitaxel and lithium. Cell calcium 23 32871457
2022 Activation of TRPV4 Induces Exocytosis and Ferroptosis in Human Melanoma Cells. International journal of molecular sciences 22 35456964
2021 Emerging Role of Transient Receptor Potential Vanilloid 4 (TRPV4) Ion Channel in Acute and Chronic Itch. International journal of molecular sciences 22 34299208
2023 The CaSR/TRPV4 coupling mediates pro-inflammatory macrophage function. Acta physiologica (Oxford, England) 21 36606511
2021 Mitochondria regulate TRPV4-mediated release of ATP. British journal of pharmacology 20 34605007
2021 TRPV4 mediates cell damage induced by hyperphysiological compression and regulates COX2/PGE2 in intervertebral discs. JOR spine 20 34611585
2019 Physiological and Pathological Role of TRPV1, TRPV2 and TRPV4 Channels in Heart. Current cardiology reviews 20 30848206
2021 Regulation of TGFβ Signalling by TRPV4 in Chondrocytes. Cells 19 33805168
2024 Structural Pharmacology of TRPV4 Antagonists. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 18 38659239
2017 Role of Nonneuronal TRPV4 Signaling in Inflammatory Processes. Advances in pharmacology (San Diego, Calif.) 18 28528666
2023 Cell-specific NFIA upregulation promotes epileptogenesis by TRPV4-mediated astrocyte reactivity. Journal of neuroinflammation 17 37880726
2023 TRPV4 channels promote vascular permeability in retinal vascular disease. Experimental eye research 16 36773739
2023 Transient Receptor Potential Vanilloid (TRPV4) channel inhibition: A novel promising approach for the treatment of lung diseases. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 16 37178575
2022 Role of TRPV4 in skeletal function and its mutant-mediated skeletal disorders. Current topics in membranes 16 36210150
2022 miRNA-203b-3p Induces Acute and Chronic Pruritus through 5-HTR2B and TRPV4. The Journal of investigative dermatology 15 36049541
2022 The role of TRPV4 channels in cutaneous epithelia. Current topics in membranes 15 36210147
2022 TRPV4 Promotes Metastasis in Melanoma by Regulating Cell Motility through Cytoskeletal Rearrangement. International journal of molecular sciences 15 36499486

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