Affinage

TRPV4

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

Length
871 aa
Mass
98.3 kDa
Annotated
2026-04-28
100 papers in source corpus 34 papers cited in narrative 34 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TRPV4 is a polymodal, Ca2+-permeable, non-selective cation channel that integrates osmotic, mechanical, thermal, and chemical stimuli to regulate diverse cellular processes including cell volume homeostasis, cytoskeletal remodeling, inflammation, nociception, and angiogenesis. The channel, which assembles as a homotetramer, is activated by hypoosmotic cell swelling via cytochrome P450-derived epoxyeicosatrienoic acids, by phorbol derivatives (4α-PDD) and synthetic agonists (GSK1016790A) acting at the S1-S4 voltage-sensing-like domain, and is negatively regulated by intracellular Ca2+ (~406 nM IC50) and membrane cholesterol (PMID:11827975, PMID:11094154, PMID:37353478, PMID:34710431). Ca2+ influx through TRPV4 activates context-dependent downstream effectors—CaM/CaMKII, calcineurin, RhoA/ROCK, NLRP3 inflammasome, and the scramblase TMEM16F—thereby controlling actin dynamics, barrier integrity, trophoblast fusion, macrophage polarization, and mechanotransduction in chondrocytes, endothelial cells, and neurons (PMID:27029071, PMID:34663597, PMID:35670667, PMID:33707778, PMID:32130954). The N-terminal ankyrin repeat domain directly binds and suppresses RhoA, as confirmed by cryo-EM; neuropathy-causing TRPV4 mutations selectively disrupt this interaction, impairing neurite outgrowth, while skeletal dysplasia mutations do not, establishing mutation-specific pathomechanisms (PMID:33664271, PMID:37353478).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2000 High

    Identifying TRPV4 as an osmosensor resolved a long-standing question of which channel mediates swelling-activated Ca2+ entry, establishing its primary physiological stimulus.

    Evidence Heterologous expression with hypoosmotic perfusion and Ca2+ measurement

    PMID:11094154

    Open questions at the time
    • Upstream signal transduction from cell swelling to channel gating was unknown
    • No pharmacological tools or defined agonist binding site
  2. 2002 High

    Demonstrating that phorbol ester 4α-PDD directly gates TRPV4 independently of PKC, and that intracellular Ca2+ provides negative feedback (IC50 ~406 nM), defined the channel's biophysical fingerprint (PCa/PNa = 5.8, Eisenman IV selectivity) and established key gating/regulatory principles.

    Evidence Whole-cell patch-clamp and Ca2+ imaging in transfected and native endothelial cells with pharmacological dissection

    PMID:11713648 PMID:11827975

    Open questions at the time
    • Agonist binding site on the channel was unknown
    • Mechanism linking swelling to channel opening remained unresolved
  3. 2007 Medium

    Establishing that cell swelling activates TRPV4 indirectly through cytochrome P450 epoxygenase-generated EETs, and that the channel assembles as a homotetramer, resolved the lipid-mediated gating mechanism and subunit stoichiometry.

    Evidence Synthesis of electrophysiology, pharmacological, and biochemical data from multiple studies

    PMID:17217058

    Open questions at the time
    • No structural data on the tetramer
    • EET binding site on TRPV4 not mapped
    • No high-resolution gating model
  4. 2009 High

    Showing that TRPC6 acts downstream of TRPV4 in DRG neurons to mediate mechanical hyperalgesia placed TRPV4 at the apex of a nociceptive signaling cascade, linking channel activation to pain behavior.

    Evidence Single-cell RT-PCR, antisense knockdown, in vivo single-fiber recordings, and behavioral pain assays in rat

    PMID:19439599

    Open questions at the time
    • Direct physical interaction between TRPV4 and TRPC6 not demonstrated
    • Intermediate signaling steps from TRPV4 Ca2+ influx to TRPC6 activation were unclear
  5. 2016 High

    Discovery that TRPV4 endogenously suppresses endothelial Rho activity and tumor angiogenesis via the Rho/ROCK pathway revealed TRPV4 as a negative regulator of mechanosensitivity in vascular biology, while parallel work showed TRPV4 promotes breast cancer cell invasion through actin reorganization and cell softening.

    Evidence TRPV4 KO mice and cells with RhoA activity assay, ROCK inhibitor rescue, tumor angiogenesis model; siRNA/overexpression with AFM and xenograft for cancer invasion

    PMID:27029071 PMID:27291497

    Open questions at the time
    • Molecular mechanism linking TRPV4 Ca2+ influx to RhoA suppression was unknown
    • Whether TRPV4 directly binds RhoA was unresolved
  6. 2018 High

    Identification of DDX3X as a direct TRPV4 binding partner whose nuclear translocation is driven by TRPV4-mediated Ca2+/CaM/CaMKII signaling connected the channel to RNA metabolism and viral replication, expanding its functional repertoire beyond ion transport.

    Evidence Reciprocal co-immunoprecipitation, proximity ligation assay, nuclear fractionation, CaMKII inhibition, viral infectivity assays

    PMID:29899501

    Open questions at the time
    • Structural basis of TRPV4-DDX3X interaction unknown
    • Which DDX3X substrates are regulated downstream was not defined
  7. 2019 High

    Demonstrating that TRPV4 forms nanomolar-affinity complexes with PI3Kγ and that TGF-β induces their co-translocation to the plasma membrane for myofibroblast differentiation revealed a scaffolding function of TRPV4 beyond ion conduction.

    Evidence Co-immunoprecipitation, surface biotinylation, PI3Kγ domain mutants, myofibroblast differentiation assays

    PMID:31719171

    Open questions at the time
    • Structural determinants of TRPV4-PI3Kγ binding not mapped
    • Whether channel conductance is required alongside scaffolding was not separated
  8. 2020 High

    Multiple studies in 2020 defined tissue-specific TRPV4 effector pathways: calcineurin-dependent allergic sensitization in airway club cells, MMP2/9-mediated alveolar barrier disruption, GSK3β-dependent chondrocyte mechanotransduction, lipocalin-2-mediated microglial neuropathic pain, and reciprocal regulation with AT1R via calcineurin.

    Evidence TRPV4 KO mice with calcineurin/MMP/GSK3β pathway dissection; microglial KO with lipocalin-2 ELISA; reciprocal co-IP and FRET for AT1R-TRPV4 coupling

    PMID:25150065 PMID:32130954 PMID:32493776 PMID:33707778 PMID:36701202

    Open questions at the time
    • How the same Ca2+ influx selects different effectors in different cell types was not resolved
    • Membrane cholesterol's regulation of TRPV4 mechanosensitivity was described pharmacologically but binding site unknown
  9. 2021 High

    Yeast two-hybrid screening and functional validation established that TRPV4's N-terminal ankyrin repeat domain directly binds and suppresses RhoA; neuropathy-causing mutations selectively disrupt this interaction while skeletal dysplasia mutations do not, revealing genotype-specific pathomechanisms.

    Evidence Yeast two-hybrid, reciprocal co-IP, patch-clamp, RhoA activity assay, domain mapping, Drosophila rescue

    PMID:33664271

    Open questions at the time
    • High-resolution structure of the TRPV4-RhoA complex was not yet available
    • Mechanism by which neuropathy mutations specifically disrupt RhoA binding while preserving channel function was unclear
  10. 2021 High

    TRPV4-mediated Ca2+ influx was shown to activate macrophage NLRP3 inflammasome specifically in response to crystalline stimuli, establishing TRPV4 as a selective upstream sensor in gouty arthritis inflammation.

    Evidence TRPV4 KO mice, patch-clamp in synovial macrophages and human PBMCs, mouse gout model

    PMID:34663597

    Open questions at the time
    • How TRPV4 distinguishes crystalline from non-crystalline NLRP3 activators mechanistically was not explained
    • Whether TRPV4 is directly mechanically activated by crystals or senses downstream membrane perturbation was unresolved
  11. 2022 High

    Functional coupling of TRPV4 with the Ca2+-activated scramblase TMEM16F in Ca2+ microdomains was shown to be required for human trophoblast syncytialization, linking TRPV4 to placental development.

    Evidence Patch-clamp electrophysiology, Ca2+ imaging, siRNA knockdown, syncytialization assay in human trophoblast line

    PMID:35670667

    Open questions at the time
    • Physical interaction between TRPV4 and TMEM16F not demonstrated
    • Relevance to in vivo placentation not tested
  12. 2023 High

    Cryo-EM structures of human TRPV4 resolved the agonist (4α-PDD) and antagonist (HC-067047) binding sites within the S1-S4 VSLD, revealed the RhoA binding interface on the ankyrin repeat domain, and defined a π-to-α S6 helix transition as the structural basis of channel closure.

    Evidence Cryo-electron microscopy with functional and disease-mutation validation

    PMID:37353478

    Open questions at the time
    • Structure in a lipid environment with EET-bound state not determined
    • Gating transitions captured in only a few states; full conformational cycle unresolved
  13. 2024 High

    Additional cryo-EM structures with potent antagonists revealed an extended VSLD pocket and an apparent fourfold-to-twofold symmetry transition upon inhibitor binding, expanding the druggable landscape of TRPV4.

    Evidence Cryo-EM, molecular dynamics simulation, functional electrophysiology

    PMID:38659239

    Open questions at the time
    • Symmetry-breaking mechanism and its functional significance for gating kinetics not fully understood
    • No structures with EET or thermal stimuli captured

Open questions

Synthesis pass · forward-looking unresolved questions
  • How TRPV4 selects among its diverse downstream effectors (CaMKII, calcineurin, RhoA, NLRP3, TMEM16F) in a cell-type-specific manner, and how mechanical versus chemical gating converges on the same pore, remain central unresolved questions.
  • No unified model for cell-type-specific effector selection
  • Structural basis of mechanical gating not captured
  • EET-bound channel structure lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 4 GO:0098772 molecular function regulator activity 3 GO:0140299 molecular sensor activity 3
Localization
GO:0005886 plasma membrane 4 GO:0005856 cytoskeleton 3 GO:0005768 endosome 1
Pathway
R-HSA-162582 Signal Transduction 7 R-HSA-112316 Neuronal System 3 R-HSA-168256 Immune System 3 R-HSA-382551 Transport of small molecules 3 R-HSA-1266738 Developmental Biology 1
Partners
AGTR1ANO6CASRDDX3XPIK3CGRHOATRPC6
Complex memberships
TRPV4 homotetramer

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 Phorbol derivatives (4α-PDD) directly gate TRPV4 channels independently of protein kinase C, activating an outwardly rectifying, Ca2+-permeable cation channel (PCa/PNa = 5.8) with Eisenman IV permeation sequence; intracellular Ca2+ inhibits the channel with IC50 ~406 nM; ruthenium red blocks inward currents. Whole-cell patch-clamp and Ca2+ imaging in stably/transiently transfected cells and freshly isolated endothelial cells; pharmacological dissection The Journal of biological chemistry High 11827975
2000 TRPV4 (Trp12) is activated by hypoosmotic (swelling) stimuli, mediating Ca2+ influx in response to cell volume increase. Heterologous expression in transfected cells with hypoosmotic perfusion and cytosolic Ca2+ measurement FEBS letters High 11094154
2001 Heterologous expression of TRPV4 (TRP12/OTRPC4) in HEK-293 cells produces a swelling-activated cation current with Eisenman-IV permeability sequence (PK>PCs>PNa>PLi); TRPV4 over-expression dramatically downregulates the volume-regulated anion channel (VRAC); TRPV4 current cannot be activated by reduced ionic strength or GTPγS, distinguishing it mechanistically from VRAC. Whole-cell patch-clamp in HEK-293 cells expressing TRPV4; pharmacological and ionic substitution experiments Pflugers Archiv : European journal of physiology High 11713648
2007 TRPV4-containing channels are homotetramers that cannot form heteromultimers with other TRPV isoforms; channel activation by cell swelling and endocannabinoids requires cytochrome P450 epoxygenase-dependent metabolism of arachidonic acid to epoxyeicosatrienoic acids (EETs); heat and 4α-phorbol esters share a common activation mechanism; intracellular Ca2+ has both potentiating and inhibitory effects. Review integrating electrophysiology, pharmacology, biochemical assays from multiple studies Handbook of experimental pharmacology Medium 17217058
2009 TRPC1 and TRPC6 channels cooperate with TRPV4 to mediate mechanical hyperalgesia and nociceptor sensitization; mRNAs for TRPV4, TRPC1, and TRPC6 are co-expressed in individual DRG neurons; antisense knockdown of TRPC6 (but not TRPC1) reversed mechanical hyperalgesia induced by 4α-PDD or thermal injury, placing TRPC6 downstream in the TRPV4-dependent sensitization pathway. Single-cell RT-PCR; intradermal/intrathecal antisense oligodeoxynucleotide knockdown; in vivo single-fiber recordings; behavioral pain assays in rat The Journal of neuroscience : the official journal of the Society for Neuroscience High 19439599
2009 Progesterone receptor (PR) transcriptionally represses TRPV4 expression in human airway and mammary epithelial cells and vascular smooth muscle cells; PR antagonist RU-486 or siRNA against PRA/PRB isoforms reverses this suppression; TRPV4 promoter activity is directly reduced by PR co-expression. qPCR, Western blot, siRNA, promoter-luciferase reporter assay, Ca2+ imaging and electrophysiology Pflugers Archiv : European journal of physiology High 19701771
2014 TRPV4 activation in human odontoblast-like cells (expressing TRPV4 protein confirmed by Western blot and immunocytochemistry) stimulates ATP release via a Ca2+-dependent mechanism; effect blocked by HC067047 (TRPV4 antagonist). RT-PCR, Western blot, immunocytochemistry, ratiometric Ca2+ imaging (Fura-2), luciferin-luciferase ATP assay; pharmacological blockade Journal of dental research Medium 25062738
2014 TRPV4 activation provides the Ca2+ signal necessary for proteolytic disruption of the alveolar barrier by matrix metalloproteinases MMP2 and MMP9; TRPV4 agonist GSK-1016790A increases active MMP2/9 isoforms and decreases TIMP2; pharmacological MMP2/9 blockade (SB-3CT) protects against TRPV4-induced lung injury in TRPV4+/+ but not TRPV4-/- mice. Western blot, lung wet-to-dry weight ratios, BAL protein; TRPV4 KO mice; pharmacological inhibitors; isolated perfused mouse lungs American journal of physiology. Lung cellular and molecular physiology High 25150065
2016 TRPV4 is required for breast cancer cell invasion and transendothelial migration (not proliferation); TRPV4 overexpression promotes actin reorganization, cell softening, and blebbing; TRPV4 knockdown reduces metastatic nodules in mouse xenografts without affecting tumor size. siRNA knockdown, overexpression, transendothelial migration assay, atomic force microscopy (cell stiffness), mouse xenograft model, confocal imaging Scientific reports High 27291497
2016 Absence of TRPV4 in endothelial cells leads to increased basal Rho activity and aberrant mechanosensitivity; TRPV4 endogenously suppresses tumor angiogenesis by restraining EC mechanosensitivity via the Rho/Rho kinase pathway; pharmacological inhibition of Rho/ROCK (Y-27632) normalizes the angiogenic phenotype of TRPV4KO endothelial cells. TRPV4 KO mice and endothelial cells; RhoA activity assay; proliferation/migration/tube formation assays; aortic ring sprouting; Y-27632 rescue; syngeneic tumor model Oncotarget High 27029071
2018 TRPV4 physically binds the DEAD-box RNA helicase DDX3X; TRPV4-mediated Ca2+ influx releases DDX3X from the channel and drives DDX3X nuclear translocation via calmodulin and CaM-dependent kinase II (CaMKII); this regulates DDX3X-dependent nuclear viral export and translation; TRPV4 inhibition reduces infectivity of dengue, hepatitis C and Zika viruses. Co-immunoprecipitation, proximity ligation assay, nuclear fractionation, Ca2+ imaging, siRNA knockdown, viral infectivity assays, CaMKII pharmacological inhibition Nature communications High 29899501
2019 TRPV4 forms nanomolar-affinity intracellular complexes with PI3Kγ; TGF-β induces translocation of TRPV4-PI3Kγ complexes to the plasma membrane, increasing both TRPV4 and PI3Kγ activity; only the non-catalytic N-terminal domain of PI3Kγ p110γ subunit is necessary and sufficient for TGF-β-induced TRPV4 plasma membrane recruitment and myofibroblast transdifferentiation. Co-immunoprecipitation, proximity ligation assay, surface biotinylation, gain/loss-of-function genetic approaches, p110γ domain mutants, α-SMA/collagen-1 assays, contractile force measurement Science signaling High 31719171
2019 GSK1016790A (TRPV4 agonist) stimulation causes TRPV4 internalization from the plasma membrane to recycling endosomes within 20 min via PI3K, PKC, and RhoA signaling; TRPV4 membrane density is controlled through complete and partial vesicular fusion modes. Single-molecule total internal reflection fluorescence microscopy, live-cell imaging, pharmacological inhibitors of PI3K/PKC/RhoA, Ca2+ imaging Frontiers in pharmacology Medium 30728775
2020 TRPV4 controls cytoskeletal dynamics in endometrial cancer cells via the RhoA/ROCK1 pathway, leading to LIMK/cofilin activation, which modulates F-actin and paxillin levels to regulate cell migration. Proteomics, Western blot, siRNA knockdown, TRPV4 agonist/antagonist pharmacology, migration assays, in vivo xenograft Cell death & disease Medium 33230171
2020 TRPV4 mediates Ca2+ influx in response to Aspergillus alkaline protease 1 (Alp1)-induced junction damage in bronchiolar club cells; this Ca2+ signal activates calcineurin, initiating allergic sensitization; TRPV4 is necessary and sufficient for club cell sensitization to Alp1. TRPV4 KO mice, human cohort SNP/protein analysis, calcineurin pathway dissection, in vivo lung eosinophilia model, conditional rescue Cell host & microbe High 32130954
2021 TRPV4 interacts with and controls phosphorylation of GSK3β in healthy chondrocytes in response to extracellular matrix viscoelasticity; this TRPV4-GSK3β pathway is dysfunctional in osteoarthritic chondrocytes, rendering them unable to respond to environmental mechanical changes. Alginate hydrogels of varying viscoelasticity, TRPV4 pharmacological inhibition, Western blot for GSK3β phosphorylation, Ca2+ imaging, cytokine secretion assays, human osteoarthritic chondrocytes Nature biomedical engineering High 33707778
2021 TRPV4 binds RhoA via its N-terminal intracellular domain; this interaction suppresses TRPV4 channel activity and inhibits RhoA activation, promoting neurite extension; neuropathy-causing (but not skeletal dysplasia) TRPV4 mutations disrupt TRPV4-RhoA binding and impair neurite outgrowth; RhoA inhibition restores neurite length in a fly model of TRPV4 neuropathy. Unbiased yeast two-hybrid screen, co-immunoprecipitation, patch-clamp electrophysiology, RhoA activity assay, neurite length measurement, domain mapping, Drosophila neuropathy model Nature communications High 33664271
2023 Cryo-EM structure of human TRPV4 in complex with RhoA reveals that RhoA binds the membrane-facing surface of the TRPV4 ankyrin repeat domain (N-terminal); agonist 4α-PDD and inhibitor HC-067047 bind at the base of the S1-S4 (voltage-sensing-like domain) bundle; agonist binding leads to pore opening, while channel inhibition involves a π-to-α helix transition in the pore-forming S6 helix. Cryo-electron microscopy structure determination; functional validation with known ligands and disease mutations Nature communications High 37353478
2024 Cryo-EM structures of human TRPV4 in complex with two potent antagonists show both bind the voltage-sensing-like domain (VSLD) and stabilize the channel in closed states; one antagonist binds an extended VSLD pocket distinct from the canonical site; antagonist binding induces an apparent fourfold-to-twofold symmetry transition. Cryo-electron microscopy, molecular dynamics simulation, functional electrophysiology Advanced science High 38659239
2020 Membrane cholesterol regulates TRPV4 mechanosensitivity: depletion of free membrane cholesterol with MβCD augments TRPV4 activation by agonist, cell swelling, and mechanical strain, and increases membrane expression of TRPV4; cholesterol supplementation reverses these effects; TRPV4 localizes mainly outside cholesterol-enriched lipid rafts/caveolae. MβCD cholesterol depletion/repletion, Ca2+ imaging, Xenopus oocyte electrophysiology, immunoprecipitation, immunofluorescence, co-localization analysis in human trabecular meshwork cells Journal of lipid research Medium 34710431
2020 Microglial TRPV4 mediates microglial activation and proliferation and promotes functional and structural plasticity of excitatory spinal neurons through release of lipocalin-2; genetic ablation or pharmacological blockade of TRPV4 markedly attenuates neuropathic pain behaviors in a mouse spared nerve injury model. Genetic knockout, pharmacological blockade, spared nerve injury mouse model, lipocalin-2 ELISA, electrophysiology, behavioral pain assays The Journal of clinical investigation High 36701202
2020 AT1R (angiotensin II receptor type 1) and TRPV4 are direct binding partners; angiotensin II-induced AT1R activation elicits β-arrestin-dependent inhibition and internalization of TRPV4; conversely, TRPV4 activation inhibits AT1R phosphorylation by activating the Ca2+/calmodulin-dependent phosphatase calcineurin, preventing β-arrestin recruitment and AT1R internalization. Co-immunoprecipitation, fluorescence resonance energy transfer, Ca2+ imaging, phosphate radiolabeling, β-arrestin-luciferase assay, primary mouse choroid plexus epithelial cells The Journal of biological chemistry High 32493776
2020 TRPV4 activation promotes glioblastoma invasion via the Cdc42/N-WASP signaling axis; TRPV4 co-localizes and interacts with F-actin at cellular protrusions and regulates invadopodia and filopodia formation. Co-immunoprecipitation/co-localization, TRPV4 agonist/antagonist pharmacology, siRNA knockdown, Cdc42 activity assay, invasion assays, intracranial mouse xenograft Scientific reports Medium 32843668
2018 TRPV4 promotes glioma cell migration and invasion via the AKT/Rac1 signaling pathway; activated TRPV4 promotes AKT phosphorylation leading to Rac1 activation. TRPV4 agonist (GSK1016790A)/antagonist (HC-067047) pharmacology, Rac1 activation assay, Western blot for pAKT, migration/invasion assays Biochemical and biophysical research communications Medium 29928875
2022 TRPV4 and TMEM16F are functionally coupled within Ca2+ microdomains in human trophoblasts; TRPV4-mediated Ca2+ influx activates TMEM16F (a Ca2+-activated phospholipid scramblase), which is required for trophoblast syncytialization; pharmacological inhibition or siRNA knockdown of TRPV4 reduces TMEM16F activation and trophoblast fusion. Patch-clamp electrophysiology, Ca2+ imaging, siRNA knockdown, TRPV4-specific agonist GSK1016790A, syncytialization assay in human trophoblast cell line eLife High 35670667
2021 TRPV4 activation in osteocytes via a NOX2-generated ROS-dependent mechanism leads to Ca2+ influx, CaMKII activation, and rapid sclerostin protein downregulation in response to fluid shear stress; TRPV4-mediated Ca2+ influx is required for subsequent purinergic Ca2+ oscillations, which regulate sclerostin and osterix gene expression. Pharmacological TRPV4 inhibition, NOX2 inhibition, CaMKII inhibition, purinergic receptor blockade (apyrase), fluid shear stress assay, Western blot for sclerostin protein, qPCR Bone Medium 32272228
2021 TRPV4-induced Ca2+ influx activates TMEM16F-mediated phospholipid scramblase activity in a microdomain-dependent manner; separately, mitochondria regulate TRPV4-mediated Ca2+ signaling: when mitochondrial membrane potential is depolarized, TRPV4 activation triggers ATP release via pannexin channels, which then activates purinergic receptors to trigger IP3-evoked Ca2+ release independent of extracellular Ca2+ influx. Ca2+ imaging with Cal520 in rat mesenteric artery endothelium, mitochondrial uncouplers (CCCP, rotenone), pannexin blocker (probenecid), suramin, apyrase, SERCA inhibitor, IP3R blocker, TRPV4 blocker HC067047 British journal of pharmacology Medium 34605007
2018 Shear stress sensitizes endothelial TRPV4 to agonist stimulation and links TRPV4 to muscarinic M3 receptor (Gq-coupled GPCR)-mediated vasodilation; M3 receptor activation opens TRPV4 in HEK293 cells; shear stress does not alter TRPV4 localization to endothelium. Pressure myography of rat cremaster arterioles, TRPV4 antagonists (GSK2193874, HC067047), endothelium removal, HEK293 transfection and Ca2+ imaging, TRPV4 immunostaining Pharmacological research Medium 29787869
2021 TRPV4 activation in intervertebral disc annulus fibrosus cells induces Rho/ROCK-dependent actin cytoskeleton remodeling and stress fiber formation; TRPV4-mediated Ca2+ signaling regulates mechanically-induced changes in Acan and Prg4 gene expression in AF cells. Fura-2 Ca2+ imaging, GSK1016790A agonist/GSK2193874 antagonist, F-actin staining, cyclic tensile strain, qPCR; transgenic Trpv4-LacZ reporter mouse for localization European cells & materials Medium 33620083
2022 The calcium-sensing receptor (CaSR) couples to TRPV4 channels in macrophages via PLA2/cytochrome P450 and PLC/PKC pathways to mediate Ca2+ entry; CaSR activation-induced Ca2+ signals and M1 macrophage polarization (IL-1β, TNFα) are significantly attenuated in TRPV4 KO macrophages. TRPV4 KO mice peritoneal macrophages, Ca2+ imaging, pharmacological inhibitors of PLA2/CYP450 and PLC/PKC, ELISA, qPCR, Western blot Acta physiologica Medium 36606511
2021 TRPV4 mediates NLRP3 inflammasome activation by crystalline materials (monosodium urate, etc.) in macrophages, driving IL-1β production; this requires TRPV4 expressed in synovial macrophages; crystal-induced gouty arthritis is reduced by genetic or pharmacological TRPV4 inhibition; non-crystalline NLRP3 activators do not require TRPV4. TRPV4 KO mice, pharmacological TRPV4 inhibition, patch-clamp and Ca2+ imaging in synovial macrophages and human PBMCs, in vitro NLRP3 inflammasome assay, mouse gout model Annals of the rheumatic diseases High 34663597
2022 TRPV4 activation in TG sensory neurons potentiates CGRP secretion in mouse models of TMJ inflammation and masseter muscle injury; sensory neuron-specific Trpv4 conditional knockout mice display reduced pain; CGRP receptor blockade attenuates pain, placing CGRP downstream of TRPV4. Sensory neuron-specific Trpv4 cKO mice, CGRP ELISA in multiple tissues/plasma, CGRP receptor antagonist, behavioral pain assays, immunostaining for TRPV4/CGRP co-expression The journal of pain High 36509176
2021 TRPV4 activation in chondrocytes by TGF-β signaling augments canonical TGF-β (SMAD) responses in a Ca2+/CaMKII-dependent manner; this effect requires TRPV4 activation after TGF-β stimulation (not before); RNA-seq identifies JUN and SP1 as key transcription factors in this response. Pharmacological TRPV4 activation/inhibition, siRNA knockdown, CaMKII inhibitor, SMAD reporter assay, RNA-seq analysis in chondrocytes Cells Medium 33805168
2023 Endothelial TRPV4 deletion activates YAP and VEGFR2 via the Rho/ROCK/LATS kinase pathway in a matrix stiffness-dependent manner, promoting coronary angiogenesis; TRPV4 acts as a mechanical brake on coronary angiogenesis. Endothelial-specific TRPV4 KO mice, transverse aortic constriction, RNA-seq, siRNA, Western blot, stiffness-variable ECM gels, confocal immunofluorescence Hypertension High 37702061

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 484 11827975
2000 Trp12, a novel Trp related protein from kidney. FEBS letters 248 11094154
2013 The puzzle of TRPV4 channelopathies. EMBO reports 245 23306656
2021 Cannabidiol inhibits human glioma by induction of lethal mitophagy through activating TRPV4. Autophagy 178 33629929
2009 TRPC1 and TRPC6 channels cooperate with TRPV4 to mediate mechanical hyperalgesia and nociceptor sensitization. The Journal of neuroscience : the official journal of the Society for Neuroscience 171 19439599
2014 The TRPV4 channel. Handbook of experimental pharmacology 127 24756711
2003 The TRPV4 channel: structure-function relationship and promiscuous gating behaviour. Pflugers Archiv : European journal of physiology 125 12715179
2016 TRPV4 Regulates Breast Cancer Cell Extravasation, Stiffness and Actin Cortex. Scientific reports 110 27291497
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
2016 Involvement of TRPV4 in Serotonin-Evoked Scratching. The Journal of investigative dermatology 109 26763435
2020 TRPV4-A Missing Link Between Mechanosensation and Immunity. Frontiers in immunology 99 32210976
2020 Calcium and TRPV4 promote metastasis by regulating cytoskeleton through the RhoA/ROCK1 pathway in endometrial cancer. Cell death & disease 99 33230171
2020 TRPV4: A Physio and Pathophysiologically Significant Ion Channel. International journal of molecular sciences 97 32481620
2020 Mechanical force modulates periodontal ligament stem cell characteristics during bone remodelling via TRPV4. Cell proliferation 91 32964544
2021 A dysfunctional TRPV4-GSK3β pathway prevents osteoarthritic chondrocytes from sensing changes in extracellular matrix viscoelasticity. Nature biomedical engineering 84 33707778
2007 TRPV4. Handbook of experimental pharmacology 84 17217058
2016 TRPV4 channels regulate tumor angiogenesis via modulation of Rho/Rho kinase pathway. Oncotarget 83 27029071
2023 A TRPV4-dependent neuroimmune axis in the spinal cord promotes neuropathic pain. The Journal of clinical investigation 78 36701202
2020 Club Cell TRPV4 Serves as a Damage Sensor Driving Lung Allergic Inflammation. Cell host & microbe 76 32130954
2019 The TRPV4 Agonist GSK1016790A Regulates the Membrane Expression of TRPV4 Channels. Frontiers in pharmacology 74 30728775
2012 TRPV4-associated skeletal dysplasias. American journal of medical genetics. Part C, Seminars in medical genetics 72 22791502
2008 Molecular mechanisms of TRPV4-mediated neural signaling. Annals of the New York Academy of Sciences 71 19076362
2019 Role of macrophage TRPV4 in inflammation. Laboratory investigation; a journal of technical methods and pathology 70 31645630
2014 TRPA1 and TRPV4 activation in human odontoblasts stimulates ATP release. Journal of dental research 70 25062738
2016 Modulation of TRPV4 by diverse mechanisms. The international journal of biochemistry & cell biology 69 27425399
2021 Mechanosensitive TRPV4 is required for crystal-induced inflammation. Annals of the rheumatic diseases 65 34663597
2018 The TRPV4 channel links calcium influx to DDX3X activity and viral infectivity. Nature communications 65 29899501
2014 Role of MMP2 and MMP9 in TRPV4-induced lung injury. American journal of physiology. Lung cellular and molecular physiology 64 25150065
2015 Hyperglycemia and Diabetes Downregulate the Functional Expression of TRPV4 Channels in Retinal Microvascular Endothelium. PloS one 63 26047504
2014 TRPV4: physiological role and therapeutic potential in respiratory diseases. Naunyn-Schmiedeberg's archives of pharmacology 62 25342095
2022 TRPV4 contributes to ER stress and inflammation: implications for Parkinson's disease. Journal of neuroinflammation 61 35093118
2020 Endothelial TRPV4 channels and vasodilator reactivity. Current topics in membranes 59 32402646
2010 TRPV4-mediated channelopathies. Channels (Austin, Tex.) 57 20676052
2023 Structure of human TRPV4 in complex with GTPase RhoA. Nature communications 55 37353478
2020 TRPV4 integrates matrix mechanosensing with Ca2+ signaling to regulate extracellular matrix remodeling. The FEBS journal 54 33300268
2015 TRPV4 channel activation selectively inhibits tumor endothelial cell proliferation. Scientific reports 52 26388427
2012 Human skeletal dysplasia caused by a constitutive activated transient receptor potential vanilloid 4 (TRPV4) cation channel mutation. Experimental & molecular medicine 52 23143559
2019 Activation of PTEN by inhibition of TRPV4 suppresses colon cancer development. Cell death & disease 51 31189890
2021 Membrane cholesterol regulates TRPV4 function, cytoskeletal expression, and the cellular response to tension. Journal of lipid research 50 34710431
2019 Translocation of TRPV4-PI3Kγ complexes to the plasma membrane drives myofibroblast transdifferentiation. Science signaling 48 31719171
2009 The progesterone receptor regulates the expression of TRPV4 channel. Pflugers Archiv : European journal of physiology 48 19701771
2021 Neuropathy-causing TRPV4 mutations disrupt TRPV4-RhoA interactions and impair neurite extension. Nature communications 44 33664271
2022 A novel antagonist of TRPM2 and TRPV4 channels: Carvacrol. Metabolic brain disease 43 34989943
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 38 32843668
2020 The role of TRPV4 channels in ocular function and pathologies. Experimental eye research 38 32979394
2017 The role of TRPV4 in fibrosis. Gene 38 29126921
2012 Novel insights into TRPV4 function in the kidney. Pflugers Archiv : European journal of physiology 38 23207579
2020 TRPV4 activation by thermal and mechanical stimuli in disease progression. Laboratory investigation; a journal of technical methods and pathology 36 31896814
2018 TRPV4 promotes the migration and invasion of glioma cells via AKT/Rac1 signaling. Biochemical and biophysical research communications 36 29928875
2018 TRPV4: a Sensor for Homeostasis and Pathological Events in the CNS. Molecular neurobiology 35 29582401
2018 Shear stress sensitizes TRPV4 in endothelium-dependent vasodilatation. Pharmacological research 34 29787869
2018 TRPM3/TRPV4 regulates Ca2+-mediated RANKL/NFATc1 expression in osteoblasts. Journal of molecular endocrinology 34 30328352
2022 Functional coupling between TRPV4 channel and TMEM16F modulates human trophoblast fusion. eLife 33 35670667
2016 TRPV4 ion channel as important cell sensors. Journal of anesthesia 33 27506578
2022 Diverse Roles of TRPV4 in Macrophages: A Need for Unbiased Profiling. Frontiers in immunology 32 35126384
2019 Involvement of TRPV1 and TRPV4 Channels in Retinal Angiogenesis. Investigative ophthalmology & visual science 32 31369032
2024 Electroacupuncture ameliorates neuroinflammation by inhibiting TRPV4 channel in ischemic stroke. CNS neuroscience & therapeutics 31 38334061
2022 Sensory Neuron-TRPV4 Modulates Temporomandibular Disorder Pain Via CGRP in Mice. The journal of pain 31 36509176
2021 Modulating the Mechanical Activation of TRPV4 at the Cell-Substrate Interface. Frontiers in bioengineering and biotechnology 31 33537292
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
2021 Ca2+ Signaling by TRPV4 Channels in Respiratory Function and Disease. Cells 27 33917551
2016 Increasing TRPV4 expression restores flow-induced dilation impaired in mesenteric arteries with aging. Scientific reports 27 26947561
2023 Deletion of Endothelial TRPV4 Protects Heart From Pressure Overload-Induced Hypertrophy. Hypertension (Dallas, Tex. : 1979) 26 37702061
2020 TRPV4 calcium influx controls sclerostin protein loss independent of purinergic calcium oscillations. Bone 25 32272228
2020 Leukemia cells remodel marrow adipocytes via TRPV4-dependent lipolysis. Haematologica 25 33131246
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
2022 Glucosylsphingosine evokes pruritus via activation of 5-HT2A receptor and TRPV4 in sensory neurons. British journal of pharmacology 24 34766332
2021 Role of TRPV4 channel in vasodilation and neovascularization. Microcirculation (New York, N.Y. : 1994) 24 33971061
2021 TRPing on Cell Swelling - TRPV4 Senses It. Frontiers in immunology 24 34616399
2022 Inhibition of Transient Receptor Potential Vanilloid 4 (TRPV4) Mitigates Seizures. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics 23 35182379
2020 Channels that Cooperate with TRPV4 in the Brain. Journal of molecular neuroscience : MN 23 32524421
2020 Emerging roles of the TRPV4 channel in bladder physiology and dysfunction. The Journal of physiology 23 33052604
2023 Astrocytic TRPV4 Channels and Their Role in Brain Ischemia. International journal of molecular sciences 22 37108263
2023 TRPV4 regulates osteoblast differentiation and mitochondrial function that are relevant for channelopathy. Frontiers in cell and developmental biology 22 37377733
2022 Activation of TRPV4 Induces Exocytosis and Ferroptosis in Human Melanoma Cells. International journal of molecular sciences 22 35456964
2023 Pathophysiological Roles of the TRPV4 Channel in the Heart. Cells 21 37371124
2020 Modulating TRPV4 channels with paclitaxel and lithium. Cell calcium 21 32871457
2024 The Multifaceted Functions of TRPV4 and Calcium Oscillations in Tissue Repair. International journal of molecular sciences 20 38256251
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 20 38959010
2023 The CaSR/TRPV4 coupling mediates pro-inflammatory macrophage function. Acta physiologica (Oxford, England) 20 36606511
2021 Emerging Role of Transient Receptor Potential Vanilloid 4 (TRPV4) Ion Channel in Acute and Chronic Itch. International journal of molecular sciences 20 34299208
2021 Mitochondria regulate TRPV4-mediated release of ATP. British journal of pharmacology 20 34605007
2020 The nonselective cation channel TRPV4 inhibits angiotensin II receptors. The Journal of biological chemistry 20 32493776
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
2021 Identification of TRPV4 as a novel target in invasiveness of colorectal cancer. BMC cancer 19 34814869
2023 Antagonism of TRPV4 channels partially reduces mechanotransduction in rat skeletal muscle afferents. The Journal of physiology 18 36869605
2021 TRPV4 mediates cell damage induced by hyperphysiological compression and regulates COX2/PGE2 in intervertebral discs. JOR spine 18 34611585
2020 The transient receptor potential vanilloid 4 (TRPV4) ion channel mediates protease activated receptor 1 (PAR1)-induced vascular hyperpermeability. Laboratory investigation; a journal of technical methods and pathology 18 32341518
2019 Enhanced junctional epithelial permeability in TRPV4-deficient mice. Journal of periodontal research 18 31343743
2017 Role of Nonneuronal TRPV4 Signaling in Inflammatory Processes. Advances in pharmacology (San Diego, Calif.) 18 28528666
2024 Structural Pharmacology of TRPV4 Antagonists. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 17 38659239
2021 Spatiotemporal and functional characterisation of transient receptor potential vanilloid 4 (TRPV4) in the murine intervertebral disc. European cells & materials 17 33620083
2023 Cell-specific NFIA upregulation promotes epileptogenesis by TRPV4-mediated astrocyte reactivity. Journal of neuroinflammation 16 37880726
2022 Role of TRPV4 in skeletal function and its mutant-mediated skeletal disorders. Current topics in membranes 16 36210150
2023 Transient Receptor Potential Vanilloid (TRPV4) channel inhibition: A novel promising approach for the treatment of lung diseases. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 15 37178575
2022 miRNA-203b-3p Induces Acute and Chronic Pruritus through 5-HTR2B and TRPV4. The Journal of investigative dermatology 15 36049541