Affinage

TRPV2

Transient receptor potential cation channel subfamily V member 2 · UniProt Q9Y5S1

Length
764 aa
Mass
86.0 kDa
Annotated
2026-04-28
100 papers in source corpus 46 papers cited in narrative 44 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TRPV2 is a Ca²⁺-permeable nonselective cation channel that functions as a polymodal sensor of noxious heat, mechanical force, and lipid signals, translating these stimuli into Ca²⁺ influx to drive macrophage phagocytosis, cardiac mechanotransduction, insulin secretion, thermogenesis, and cell migration. Under basal conditions TRPV2 resides predominantly in intracellular (ER) membranes and translocates to the plasma membrane via PI3K/Akt- and Rac-dependent pathways triggered by growth factors, chemotactic peptides, or mechanical stress (PMID:17154364, PMID:20854263, PMID:25677550); at the plasma membrane it generates Ca²⁺ microdomains that activate downstream effectors including PIP₂ synthesis for phagocytic receptor clustering, CaMKII in cardiomyocytes, calpain/talin cleavage in migrating cells, and CaMKK2/AMPK during replication stress (PMID:20118928, PMID:23786999, PMID:36744297, PMID:36696898). Channel gating is regulated by PIP₂ hydrolysis (desensitization), JAK1-mediated tyrosine phosphorylation at Y335/Y471/Y525 (sensitization), cholesterol occupancy of the vanilloid binding pocket (inhibition), and oxidation of M528/M607 (activation), while cryo-EM and crystallographic structures have defined distinct ligand-binding sites for CBD, 2-APB, cholesterol, and piperlongumine and revealed C₂-symmetric intermediates during pore opening (PMID:20926660, PMID:35686730, PMID:36163384, PMID:31719194, PMID:35484159, PMID:31566564). Conditional cardiac TRPV2 knockout causes rapid intercalated disc disorganization, conduction defects, and impaired IGF-1/PI3K/Akt signaling, while sarcolemmal TRPV2 accumulation drives pathological Ca²⁺ entry in dilated cardiomyopathy and Duchenne muscular dystrophy models (PMID:24874017, PMID:23786999, PMID:25616416).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1999 High

    Identification of TRPV2 (VRL-1) as a high-threshold thermosensor established that a second TRP channel senses noxious heat (>52°C) independently of TRPV1, without capsaicin or proton sensitivity.

    Evidence Heterologous expression and patch-clamp electrophysiology with defined thermal stimuli

    PMID:14622291 PMID:15665528

    Open questions at the time
    • Endogenous in vivo heat-sensing role later questioned by knockout studies
    • Species-dependent activation differences not yet recognized
  2. 2004 High

    Discovery that 2-APB directly activates TRPV2 provided the first widely used chemical agonist and suggested a shared activation mechanism across TRPV1–3.

    Evidence Calcium imaging and electrophysiology in HEK293 cells and Xenopus oocytes

    PMID:15194687 PMID:17217057

    Open questions at the time
    • 2-APB binding site unknown at this time
    • Mechanism of activation not structurally resolved
  3. 2007 High

    Demonstration that PI3K-dependent translocation from ER to plasma membrane is required for macrophage Ca²⁺ entry and migration established the regulated trafficking paradigm central to TRPV2 biology.

    Evidence GFP-TRPV2 live imaging, patch-clamp, PI3K inhibitor, pertussis toxin, siRNA, and dominant-negative TRPV2 in macrophages

    PMID:16533525 PMID:17154364

    Open questions at the time
    • Direct mechanism coupling PI3K to vesicle insertion not defined
    • Whether PI3K also modulates channel gating independently of trafficking was debated
  4. 2008 High

    CBD was identified as a potent TRPV2 agonist (EC₅₀ ~3.7 µM), and insulin was shown to drive TRPV2 translocation in β-cells potentiating glucose-stimulated insulin secretion, broadening the channel's physiological ligand and tissue repertoire.

    Evidence Ca²⁺ mobilization, siRNA knockdown, CGRP release in DRG neurons; GFP-TRPV2 translocation imaging and shRNA in β-cells with insulin receptor KO

    PMID:18550765 PMID:18984736

    Open questions at the time
    • CBD binding site unknown
    • Molecular mechanism of insulin-induced translocation not fully resolved
  5. 2010 High

    TRPV2 was shown to be essential for macrophage phagocytosis through a mechanism linking channel-mediated depolarization to PIP₂ synthesis and phagocytic receptor clustering, with knockout mice exhibiting accelerated mortality to bacterial infection.

    Evidence TRPV2 KO macrophages, phagocytosis assays, PIP₂ measurement, live imaging, in vivo Listeria infection model

    PMID:20118928

    Open questions at the time
    • How depolarization specifically promotes PIP₂ synthesis not fully explained
    • Relative contribution of TRPV2 vs other channels in innate immunity unclear
  6. 2010 High

    PIP₂ hydrolysis was identified as the mechanism of Ca²⁺-dependent TRPV2 desensitization, independent of calmodulin, resolving a key question about negative feedback on channel activity.

    Evidence Simultaneous confocal PIP₂ probe imaging and patch-clamp electrophysiology with calmodulin inhibitors

    PMID:20926660

    Open questions at the time
    • Whether PIP₂ binds directly to TRPV2 or acts indirectly not structurally resolved
    • Calmodulin C-terminal binding site identified in vitro (PMID:20686800) but functional significance in full-length channel not established
  7. 2014 High

    Conditional cardiac knockout revealed that TRPV2 is essential for maintaining intercalated disc integrity, conduction, and Ca²⁺ handling through IGF-1/PI3K/Akt signaling, establishing its non-redundant role in cardiac mechanotransduction.

    Evidence Cardiac-specific inducible TRPV2 KO mice with echocardiography, single-myocyte Ca²⁺ imaging, and IGF-1 rescue

    PMID:24874017

    Open questions at the time
    • Direct mechanosensing mechanism in cardiomyocytes not defined
    • Whether TRPV2 functions as a primary mechanosensor or secondary effector unresolved
  8. 2016 High

    First cryo-EM structures of TRPV2 (~4–5 Å) revealed the overall architecture including dual pore constrictions and suggested that ankyrin-repeat domain rotation couples to pore opening via the TRP domain, providing the structural foundation for gating models.

    Evidence Cryo-EM of full-length rabbit TRPV2 with structural comparison to TRPV1

    PMID:26779611 PMID:27021073

    Open questions at the time
    • Resolution insufficient for atomic detail of ligand binding
    • No agonist-bound structures at this stage
  9. 2016 High

    TRPV2 KO mice showed impaired brown adipose thermogenesis and cold intolerance, identifying an unexpected physiological role for the channel in energy metabolism beyond sensory neurons.

    Evidence TRPV2 KO mice, β-adrenergic stimulation, thermogenic gene expression, body temperature, Ca²⁺ chelation

    PMID:26882545

    Open questions at the time
    • Molecular mechanism linking TRPV2 Ca²⁺ to thermogenic gene expression not fully defined
    • Cell-type specificity of TRPV2 action in BAT not resolved
  10. 2018 High

    High-resolution crystal and cryo-EM structures (3.1–4.0 Å) of RTx-bound and turret-modified TRPV2 revealed that agonist binding induces two-fold symmetric selectivity filter opening permitting large organic cation permeation, and that the pore turret couples lipid binding to upper gate conformation.

    Evidence X-ray crystallography and cryo-EM of rabbit and rat TRPV2 with RTx, Ca²⁺, and turret modifications

    PMID:29728656 PMID:30598551

    Open questions at the time
    • Physiological relevance of C₂-symmetric intermediate unclear
    • Full gating cycle not captured
  11. 2018 High

    Sensory neuron-specific TRPV2 KO established the channel as a bona fide mechanical nociceptor for high-threshold stimuli, while its role as an in vivo heat sensor in mammals was not confirmed.

    Evidence Conditional KO (Advillin-Cre), behavioral testing (tail-pressure, von Frey, heat), stretch-evoked Ca²⁺ imaging

    PMID:30429536

    Open questions at the time
    • Molecular mechanism of mechanosensitivity (direct vs indirect) not resolved
    • Whether TRPV2 senses membrane stretch directly or through accessory proteins unclear
  12. 2019 High

    CBD and RTx binding sites were structurally mapped—CBD to a novel S5–S6 inter-subunit pocket and RTx inducing C₂-symmetric intermediates in native lipid—establishing that TRPV2 harbors multiple distinct ligand-binding sites that can drive different conformational pathways.

    Evidence Cryo-EM of rat TRPV2 in nanodiscs (apo and CBD-bound), rabbit TRPV2 with RTx in nanodiscs and amphipol; mutagenesis and electrophysiology

    PMID:31090543 PMID:31566564

    Open questions at the time
    • How CBD and RTx pathways converge on pore opening not fully integrated
    • Endogenous lipid ligands occupying these sites not identified
  13. 2019 High

    Oxidation of M528 and M607 was identified as a direct gating mechanism that activates and sensitizes TRPV2 in a temperature-dependent manner, linking ROS signaling to channel function and macrophage phagocytosis.

    Evidence Inside-out patch-clamp, M528I/M607I mutagenesis, mass spectrometry, phagocytosis assay with reducing agents

    PMID:31719194

    Open questions at the time
    • Structural basis of oxidation-induced conformational change unknown
    • Relative contribution of oxidation vs other gating stimuli in vivo not quantified
  14. 2022 High

    High-resolution cryo-EM (2.8–3.3 Å) revealed cholesterol bound in the vanilloid pocket inhibiting TRPV2, and showed estradiol potentiates activation by displacing cholesterol; the 2-APB binding site was mapped to the S5/S4-S5 linker interface, establishing the structural basis for lipid and small-molecule modulation of the vanilloid pocket.

    Evidence Cryo-EM with cholesterol, MβCD-treated, estradiol+2-APB, and CBD+2-APB states; mutagenesis of His521 and Arg539; electrophysiology

    PMID:35484159 PMID:36163384

    Open questions at the time
    • Whether cholesterol regulation operates in vivo under physiological conditions not tested
    • Full integration of all ligand sites into a unified gating model not achieved
  15. 2022 High

    JAK1 was identified as the kinase phosphorylating TRPV2 at Y335/Y471/Y525 to sensitize channel activity, with PTPN1 as the opposing phosphatase, establishing a reversible post-translational regulatory axis critical for macrophage phagocytosis.

    Evidence Electrophysiology in macrophages and DRG neurons, mutagenesis, kinase/phosphatase assays, siRNA of JAK1/PTPN1, phagocytosis assay

    PMID:35686730

    Open questions at the time
    • Signaling events upstream of JAK1 that trigger TRPV2 phosphorylation not defined
    • Whether other kinases contribute in different cell types unknown
  16. 2023 High

    A cGAS–STING–TRPV2 axis was discovered in which replication stress activates cGAS/STING, causing STING dissociation from TRPV2 at the ER, derepressing TRPV2-mediated Ca²⁺ release that activates CaMKK2/AMPK to protect stalled replication forks from Exo1 degradation.

    Evidence TRPV2 KO/KD, cGAS/STING epistasis, Co-IP of STING–TRPV2, Ca²⁺ imaging, fork protection assays

    PMID:36696898

    Open questions at the time
    • Whether STING directly gates TRPV2 or acts through an intermediary not clear
    • Structural basis of STING–TRPV2 interaction unknown
    • Generalizability beyond the cell lines tested not established
  17. 2023 High

    TRPV2 was shown to localize to leading edges and nascent adhesions in invasive melanoma, where it drives Ca²⁺-dependent calpain activation, talin cleavage, and F-actin reorganization to promote migration and metastasis.

    Evidence siRNA knockdown, live imaging of TRPV2 localization, calpain/talin cleavage assays, in vivo xenograft metastasis model

    PMID:36744297

    Open questions at the time
    • Whether TRPV2 is activated by mechanical cues at the leading edge or by lipid/chemical signals not distinguished
    • Therapeutic relevance of TRPV2 inhibition in metastasis not clinically validated

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include whether TRPV2 is a direct mechanosensor or requires accessory proteins, the identity of endogenous lipid ligands occupying the vanilloid and CBD pockets, a unified structural model integrating all gating stimuli, and the in vivo relevance of TRPV2 as a thermosensor in mammals.
  • Direct vs indirect mechanosensitivity remains unresolved
  • No endogenous lipid ligands confirmed for the CBD or vanilloid pockets
  • Complete gating cycle with all modulators not structurally captured

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 6 GO:0140299 molecular sensor activity 3
Localization
GO:0005886 plasma membrane 7 GO:0005783 endoplasmic reticulum 3
Pathway
R-HSA-162582 Signal Transduction 6 R-HSA-168256 Immune System 5
Partners
JAK1LRMDAPTPN1STING1

Evidence

Reading pass · 44 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 TRPV2 (VRL-1) is a nonselective cation channel activated by noxious heat (>52°C), expressed in medium- to large-diameter primary sensory neurons, and distinct from TRPV1 in its thermal threshold and lack of capsaicin/proton sensitivity. Heterologous expression, electrophysiology (patch-clamp), in vitro heat stimulation assays Nature (referenced in corpus via PMID:14622291 background) High 14622291 15665528
2004 2-aminoethoxydiphenyl borate (2-APB) directly activates TRPV1, TRPV2, and TRPV3 but not TRPV4, TRPV5, or TRPV6 in HEK293 cells, and potentiates heat- and capsaicin-evoked responses, suggesting a common activation mechanism shared by TRPV1–3. Calcium imaging, electrophysiology in HEK293 cells and Xenopus oocytes, pharmacological characterization The Journal of biological chemistry High 15194687 17217057
2006 PI3-kinase promotes TRPV2 channel activity independently of channel translocation to the plasma membrane, as demonstrated by cytotoxicity assays and direct cell-surface expression measurements in stably transfected cells. Cytotoxicity assays, surface expression measurement, PI3K inhibitor (LY294002), stable transfection in HEK cells Cell calcium Medium 16533525
2007 Chemotactic peptide fMLP induces translocation of TRPV2 from the endoplasmic reticulum to the plasma membrane in macrophages via a PI3-kinase/pertussis toxin-sensitive (Gi/o) pathway, and this translocation is required for fMLP-induced calcium entry and macrophage migration. GFP-TRPV2 live imaging, whole-cell patch-clamp, PI3K inhibitor (LY294002), pertussis toxin, siRNA knockdown, dominant-negative TRPV2 Journal of cellular physiology High 17154364
2007 Species-dependent differences exist in TRPV2 activation: mouse and rat TRPV2 are robustly activated by heat (>53°C) and 2-APB in HEK293 cells, whereas human TRPV2 is not detectably activated by either stimulus. Chimeric and deletion studies show both the N- and C-terminal cytoplasmic domains of rat TRPV2 are important for heat and 2-APB responses and can act in trans. Calcium imaging, electrophysiology, chimera/deletion mutagenesis in HEK293 cells The Journal of biological chemistry High 17395593
2008 Cannabidiol (CBD) activates TRPV2 (EC50 = 3.7 µM) and evokes CGRP release from dorsal root ganglion neurons in a TRPV1- and cannabinoid-receptor-independent, extracellular Ca2+-dependent manner, as confirmed by siRNA knockdown of TRPV2. Calcium mobilization assays, electrophysiology, siRNA knockdown, CGRP release assay, ruthenium red block The Journal of neuroscience High 18550765
2008 Insulin induces translocation of TRPV2 from the cytoplasm/ER to the plasma membrane in pancreatic β-cells via the insulin receptor/PI3K pathway, increasing calcium entry and potentiating glucose-stimulated insulin secretion. GFP/c-Myc-tagged TRPV2 translocation imaging, Fura-2 calcium imaging, shRNA knockdown, insulin receptor knockout β-cells, tranilast pharmacology Diabetes High 18984736
2009 Lysophospholipids (lysophosphatidylcholine and lysophosphatidylinositol) activate TRPV2 via Gq/Go-protein and PI3,4-kinase signaling, causing TRPV2 translocation to the plasma membrane and stimulating prostate cancer cell migration. Calcium imaging, pharmacology (Gq/Go inhibitors, PI3K inhibitor), TRPV2 surface trafficking assay, migration assays Biochimica et biophysica acta Medium 19321128
2010 TRPV2 is required for macrophage particle binding and phagocytosis; it is recruited to the nascent phagosome, depolarizes the plasma membrane, and this depolarization increases PtdIns(4,5)P2 synthesis, triggering actin depolymerization necessary for phagocytic receptor clustering. TRPV2-deficient mice show accelerated mortality to Listeria monocytogenes. TRPV2 knockout macrophages, phagocytosis assays (zymosan, IgG, complement), live imaging, PtdIns(4,5)P2 measurement, in vivo infection model Nature immunology High 20118928
2010 Ca2+-dependent desensitization of TRPV2 is mediated by hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) and is independent of calmodulin, as shown by simultaneous confocal imaging of a fluorescent PIP2-binding probe and electrophysiological recording. Whole-cell patch-clamp, confocal imaging of PIP2-binding probe, calmodulin inhibitors, mutant calmodulin coexpression The Journal of neuroscience High 20926660
2010 RANKL-induced TRPV2 expression in preosteoclasts drives Ca2+ oscillations and activates NFATc1, promoting osteoclastogenesis; TRPV2 silencing reduces Ca2+ oscillation frequency, NFATc1 nuclear translocation, and osteoclast differentiation. DNA microarray, siRNA knockdown, patch-clamp, Ca2+ imaging, NFATc1 nuclear translocation assay Cell calcium Medium 20980052
2010 PI3K/Akt signaling promotes insulin-induced TRPV2 translocation to the plasma membrane in pancreatic β-cells, accelerating first-phase glucose-stimulated insulin secretion; this is blocked by PI3K inhibition, tranilast, or TRPV2 shRNA. Total internal reflection fluorescent microscopy, Ca2+ imaging, shRNA knockdown, PI3K inhibitor, tranilast The Biochemical journal High 20854263
2012 TRPV2 localizes to podosomes in macrophages and increases submembrane Ca2+ concentration ([Ca2+]pm) at these sites; elevated [Ca2+]pm activates Pyk2 phosphorylation and negatively regulates podosome assembly; fMLP increases TRPV2 at the podosome. TIRFM imaging, c-Myc tagged TRPV2 surface expression, ruthenium red pharmacology, dominant-negative Pyk2, siRNA knockdown Cell calcium Medium 22226146
2013 TRPV2 sarcolemmal accumulation in dilated cardiomyopathy (DCM) drives pathological Ca2+ entry and activates CaMKII and ROS production; blocking sarcolemmal TRPV2 accumulation (via N-terminal domain overexpression or tranilast) reduces ventricular dilation, fibrosis, and improves survival in DCM animal models. Immunological and cell physiological analyses, Western blot, transgenic/adenoviral overexpression of TRPV2 N-terminal domain, CaMKII phosphorylation assay, ROS measurement, in vivo DCM models Cardiovascular research High 23786999
2014 TRPV2 is critical for cardiac structure and function: conditional TRPV2 knockout in adult mouse hearts causes rapid intercalated disc disorganization, conduction defects, impaired Ca2+ handling, and reduced IGF-1/PI3K/Akt signaling; IGF-1 administration partially rescues these defects. Cardiac-specific inducible TRPV2 knockout mice, echocardiography, Ca2+ imaging of single myocytes, intercalated disc morphology, IGF-1 rescue experiment, stretch-induced Ca2+ and IGF-1 secretion assays Nature communications High 24874017
2015 TRPV2 is translocated to the sarcolemma and T-tubules in dystrophic mdx cardiomyocytes (overexpressed ~2-fold), mediating abnormal stretch-activated Ca2+ influx in Duchenne muscular dystrophy; pore-blocking antibodies and siRNA ablation of TRPV2 protect cells from stress-induced Ca2+ signals. Western blot, immunocytochemistry, biotinylation assay, pharmacological modulators, pore-blocking antibodies, siRNA, confocal Ca2+ imaging Cardiovascular research High 25616416
2015 Focal mechanical stress induces TRPV2 translocation to the stressed membrane site via a PI3K/Rac-dependent mechanism, increasing local submembrane Ca2+ concentration; this is blocked by gadolinium and LY294002. GFP-TRPV2 live imaging, RFP-Akt co-imaging, ruthenium red pharmacology, PI3K inhibitor, dominant-negative Rac, siRNA knockdown Physiological reports Medium 25677550
2016 Cryo-EM structure of rabbit TRPV2 at ~4 Å reveals that S6 (gate-forming helix) adopts a different conformation than TRPV1, and structural comparisons suggest that rotation of the ankyrin-repeat domain couples to pore opening via the TRP domain, which can be modulated by S6 secondary structure rearrangements. Cryo-electron microscopy (~4 Å resolution), structural comparison with TRPV1 Nature structural & molecular biology High 26779611
2016 Full-length TRPV2 cryo-EM structure (~5 Å) reveals two constrictions (upper and lower gates) similar to TRPV1, but with wider upper and lower gates in the agonist-free state compared to closed and agonist-activated TRPV1, providing structural basis for TRPV channel diversity. Cryo-electron microscopy (~5 Å resolution), structural comparison with TRPV1 Nature communications High 27021073
2016 TRPV2 is required for thermogenesis in brown adipose tissue: TRPV2 KO mice show reduced expression of thermogenic genes, impaired β-adrenergic-stimulated thermogenesis, cold intolerance, and increased adiposity; intracellular Ca2+ reduction mimics the KO phenotype. TRPV2 knockout mice, β-adrenergic stimulation, thermogenic gene expression, body temperature measurement, calcium chelation EMBO reports High 26882545
2016 Heat activation of TRPV2 exhibits strong use dependence: prior heat stimulation lowers temperature activation threshold and slope sensitivity, and sensitizes agonist responses, while prior agonist activation does not sensitize heat responses. This indicates separate temperature-sensing and agonist-activation pathways within the channel. Whole-cell and excised patch electrophysiology with defined heat and agonist protocols Biophysical journal High 27074678
2016 TRPV2 activation by LL-37 peptide promotes cancer cell migration via PI3K/AKT-dependent recruitment of TRPV2 to pseudopodia, with Ca2+ entry through TRPV2 cooperating with K+ efflux through BKCa channels; D-enantiomer of LL-37 produces identical effects, suggesting membrane physical property modification rather than receptor binding is the mechanism. Ca2+ imaging, siRNA knockdown, PI3K inhibitor, migration assays, membrane fluidity measurement Oncotarget Medium 26993604
2016 TRPV2 activation inhibits brown adipocyte differentiation in a dose-dependent manner during early differentiation; this inhibition is reversed by a TRPV2 antagonist and is absent in TRPV2 KO cells; calcineurin inhibitors partially rescue the inhibition, implicating a calcineurin-dependent pathway. TRPV2 agonists/antagonists, TRPV2 KO cells, calcineurin inhibitors (cyclosporine A, FK506), differentiation assays Pflügers Archiv Medium 27318696
2016 TRPV2 contributes to stretch-activated cation currents and myogenic constriction in retinal arterioles: direct membrane stretch triggers cation currents blocked by tranilast and TRPV2 pore-blocking antibodies, and mimicked by Δ9-THC; preincubation with blocking antibodies prevents myogenic tone development. Patch-clamp electrophysiology, Fura-2 Ca2+ imaging, TRPV2 pore-blocking antibodies, Δ9-THC activation, pressure myography Investigative ophthalmology & visual science High 27784066
2017 LPI activates TRPV2 via GPR55-mediated Gq/G12/13 signaling, leading to actin reorganization and TRPV2 translocation to the plasma membrane, Ca2+ influx, and GLP-1 secretion from enteroendocrine L cells; TRPV2 blockage or silencing suppresses both LPI-induced Ca2+ elevation and GLP-1 secretion. Ca2+ imaging, siRNA knockdown, GPR55 antagonist, TRPV2 antagonist, TRPV2 translocation imaging, GLP-1 secretion assay The Journal of biological chemistry Medium 28533434
2018 Crystal structures of rabbit TRPV2 in Ca2+-bound and resiniferatoxin (RTx)+Ca2+-bound forms (3.9 Å and 3.1 Å) show that RTx binding induces two-fold symmetric opening of the selectivity filter wide enough for large organic cation permeation, establishing a structural basis for Ca2+ and large organic cation permeation. X-ray crystallography (3.1 Å and 3.9 Å), functional characterization of ion permeation Nature structural & molecular biology High 29728656
2018 TRPV2 pore turret is critical for channel activity; cryo-EM structures of rat TRPV2 with and without intact pore turret (3.6–4.0 Å) reveal fully open and partially open states with unoccupied vanilloid pockets, and suggest lipid binding to the lower gate couples to the upper gate through a pore-turret-facilitated mechanism. Cryo-EM (3.6–4.0 Å), activity assays comparing channels with and without pore turret Nature structural & molecular biology High 30598551
2018 TRPV2 is required for mechanical nociception: PSN-specific TRPV2 KO mice are deficient in tail-pressure and von Frey responses but have normal heat and tactile responses; cultured KO neurons lack fast-decay, high-threshold stretch-evoked Ca2+ responses. Conditional TRPV2 knockout mice, behavioral testing (tail-pressure, von Frey, heat), stretch-evoked Ca2+ imaging of cultured primary sensory neurons Scientific reports High 30429536
2019 CBD binds to a hydrophobic pocket between S5 and S6 helices of adjacent TRPV2 subunits (distinct from known TRP ligand sites), and the S4-S5 linker plays a critical role in gating upon CBD binding; cryo-EM reveals two distinct apo states in lipid nanodiscs. Cryo-EM of full-length rat TRPV2 in nanodiscs (apo and CBD-bound states), mutagenesis, electrophysiology eLife High 31566564
2019 Oxidation of methionine residues M528 and M607 activates and sensitizes TRPV2 in a temperature-dependent manner; substitution of both residues to isoleucine almost abolishes oxidation-induced gating; this mechanism is relevant for macrophage phagocytosis, which is reduced by reducing agents or ROS scavengers. Inside-out patch-clamp, site-directed mutagenesis (M528I, M607I), mass spectrometry of purified rat TRPV2, macrophage phagocytosis assay, DTT/methionine sulfoxide reductase treatment PNAS High 31719194
2019 Resiniferatoxin (RTx) induces two-fold symmetric conformations of TRPV2 both in amphipol and in lipid nanodiscs, with more pronounced two-fold symmetry in the native-like lipid environment, indicating symmetry transitions are part of the TRPV2 gating pathway. Cryo-EM of full-length rabbit TRPV2 with RTx in nanodiscs and amphipol eLife High 31090543
2010 A calmodulin (CaM) binding site exists in the C-terminal domain of TRPV2 (residues 654–683, 1-5-10 motif); single mutations R679A and K681A reduce CaM binding affinity by 50%, and double mutation K661A/K664A reduces affinity by 75%, demonstrating Ca2+-dependent CaM regulation of TRPV2. In vitro calmodulin binding assays, site-directed mutagenesis of C-terminal peptides Amino acids Medium 20686800
2021 Piperlongumine (PL) binds to a transient allosteric pocket in TRPV2 (cryo-EM structure); Arg539 and Thr522 are key residues for PL's antagonistic effect on Ca2+ influx; TRPV2 downregulation reduces PL sensitivity and ROS production in glioblastoma cells. Cryo-EM of full-length rat TRPV2 with PL, Ca2+ imaging, mutagenesis (Arg539, Thr522), siRNA knockdown, ROS measurement, in vivo orthotopic GBM models ACS central science High 34079902
2022 2-APB binds to a TRPV2-specific site at the interface of S5 of one monomer and the S4-S5 linker of the adjacent monomer (cryo-EM); His521 and Arg539 are key for 2-APB activation; CBD and 2-APB can bind simultaneously to TRPV2 with synergistic activation. Cryo-EM of rat TRPV2 in lipid nanodiscs with 2-APB and CBD, in silico docking, electrophysiology, mutagenesis (His521, Arg539) Nature communications High 35484159
2022 Cholesterol binds inside the vanilloid binding pocket (VBP) of TRPV2 in a 'head down, tail up' configuration and antagonizes ligand activation; estradiol potentiates TRPV2 activation by 2-APB by displacing cholesterol from VBP; cryo-EM resolves cholesterol, MβCD-treated, and E2+2-APB structures at 2.8–3.3 Å. Cryo-EM at 2.8–3.3 Å, methyl-β-cyclodextrin cholesterol depletion, electrophysiology, functional assays Nature chemical biology High 36163384
2022 JAK1 phosphorylates TRPV2 at Tyr335, Tyr471, and Tyr525, altering its chemical and thermal sensitivities; PTPN1 dephosphorylates these sites; JAK1-mediated phosphorylation is required for maintaining TRPV2 activity and macrophage phagocytic ability. Electrophysiology in bone marrow-derived macrophages and DRG neurons, mutagenesis, kinase/phosphatase assays, siRNA knockdown of JAK1 and PTPN1, phagocytosis assays eLife High 35686730
2022 TRPV2 in myeloid cells facilitates virus penetration by promoting cell membrane tension and mobility through the Ca2+-LRMDA axis; TRPV2 KO suppresses viral infection and reduces membrane tension; Ca2+-impermeable TRPV2E572Q fails to rescue viral infection in KO cells; LRMDA knockdown phenocopies TRPV2 KO. Conditional TRPV2 KO (LyZ2-Cre;Trpv2fl/fl), TRPV2E572Q reconstitution, LRMDA knockdown, membrane tension measurement, viral infection assays (HSV-1, VSV), in vivo mouse infection model Advanced science High 36261399
2023 Replication stress generates cytosolic ssDNA and dsDNA that activate cGAS, producing cGAMP which binds to STING, causing STING dissociation from TRPV2 and derepression of TRPV2, leading to Ca2+ release from the ER and activation of CaMKK2/AMPK to protect stalled replication forks from Exo1-mediated degradation. TRPV2 KO/knockdown, cGAS/STING epistasis (genetic and pharmacological), Ca2+ imaging, STING-TRPV2 interaction (Co-IP), fork protection assays, Exo1 degradation assays Molecular cell High 36696898
2023 CBD sensitizes TRPV2 responses to 2-APB by over two orders of magnitude; cryo-EM reveals a new small-molecule binding site in the pore domain of rTRPV2 in addition to the known CBD site; strong sensitization is TRPV2/TRPV3-specific and does not originate solely from amino acid differences at the CBD or pore domain sites. Patch-clamp electrophysiology, cryo-EM, mutagenesis at non-conserved positions between rTRPV2 and rTRPV1 eLife High 37199723
2023 TRPV2 localizes to the leading edge and nascent adhesions of invasive melanoma cells, regulating Ca2+-mediated calpain activation and talin cleavage, as well as F-actin organization, thereby promoting migration and invasion; TRPV2 silencing in highly metastatic cells prevents aggressive in vitro and in vivo behavior. siRNA knockdown, live imaging of TRPV2 localization (leading edge/adhesions), calpain activity assay, talin cleavage assay, F-actin analysis, in vivo xenograft metastasis assay EMBO reports High 36744297
2019 TRPV2 mediates cell swelling (hypotonic stimulation)-induced Ca2+ influx and insulin secretion in mouse pancreatic β-cells; probenecid (TRPV2 activator) elevates [Ca2+]c in β-cells, and TRPV2 siRNA knockdown reduces both hypotonic Ca2+ response and insulin secretion. Fura-2 Ca2+ imaging, siRNA knockdown, ruthenium red/tranilast pharmacology, insulin secretion assay from isolated islets American journal of physiology. Cell physiology Medium 30649920
2019 TRPV2 stimulation suppresses Rac1 and RhoA activation in rheumatoid arthritis fibroblast-like synoviocytes (FLS), reduces integrin localization at the plasma membrane, decreases organized actin filaments, and inhibits FLS invasion; RhoA activators override TRPV2-induced suppression. TRPV2 stimulation assays, Rac1/RhoA activation assays, integrin localization, actin staining, invasion assays, RhoA activator rescue International immunopharmacology Medium 30851707
2018 Phagocytosis in primary human macrophages requires TRPV2-mediated Ca2+ influx, and TRPV2 must be localized to lipid rafts to be functional; P. aeruginosa recruits TRPV2 to the cell surface; cystic fibrosis macrophages have deficient TRPV2 function contributing to impaired phagocytosis. Ca2+ imaging, lipid raft fractionation, TRPV2 surface recruitment assay, phagocytosis assays, siRNA knockdown Scientific reports Medium 29523858
2023 A selective TRPV2 inhibitor (IV2-1) blocks TRPV2-mediated Ca2+ influx and shapes Ca2+ microdomains at the cell margin in macrophages; TRPV2 inhibition reduces phagocytosis and LPS-induced migration, while TRPV2 activation promotes migration; TRPV2-generated Ca2+ microdomains are important for phagocytosis and migration. Ca2+ influx assay (HEK293 expressing rat TRPV2), patch-clamp, TIRFM Ca2+ microdomain imaging in macrophages, siRNA knockdown, phagocytosis and migration assays British journal of pharmacology High 37254803

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 2-aminoethoxydiphenyl borate is a common activator of TRPV1, TRPV2, and TRPV3. The Journal of biological chemistry 419 15194687
2008 TRPV2 is activated by cannabidiol and mediates CGRP release in cultured rat dorsal root ganglion neurons. The Journal of neuroscience : the official journal of the Society for Neuroscience 308 18550765
2010 TRPV2 has a pivotal role in macrophage particle binding and phagocytosis. Nature immunology 256 20118928
2016 Cryo-electron microscopy structure of the TRPV2 ion channel. Nature structural & molecular biology 218 26779611
2004 Nociceptors lacking TRPV1 and TRPV2 have normal heat responses. The Journal of neuroscience : the official journal of the Society for Neuroscience 210 15254097
2010 Role of cationic channel TRPV2 in promoting prostate cancer migration and progression to androgen resistance. Cancer research 183 20103638
2001 Identification and characterization of a novel human vanilloid receptor-like protein, VRL-2. Physiological genomics 181 11160995
2009 Lysophospholipids stimulate prostate cancer cell migration via TRPV2 channel activation. Biochimica et biophysica acta 160 19321128
2016 Structure of the full-length TRPV2 channel by cryo-EM. Nature communications 156 27021073
2013 What do we know about the transient receptor potential vanilloid 2 (TRPV2) ion channel? The FEBS journal 151 23615321
2011 Mast-cell degranulation induced by physical stimuli involves the activation of transient-receptor-potential channel TRPV2. Physiological research 149 21574765
2007 Activation properties of heterologously expressed mammalian TRPV2: evidence for species dependence. The Journal of biological chemistry 143 17395593
2019 Molecular mechanism of TRPV2 channel modulation by cannabidiol. eLife 125 31566564
2007 Increased TRPA1, TRPM8, and TRPV2 expression in dorsal root ganglia by nerve injury. Biochemical and biophysical research communications 122 17517374
2008 Regulation of calcium-permeable TRPV2 channel by insulin in pancreatic beta-cells. Diabetes 114 18984736
2014 TRPV2 is critical for the maintenance of cardiac structure and function in mice. Nature communications 110 24874017
2007 Chemotactic peptide fMetLeuPhe induces translocation of the TRPV2 channel in macrophages. Journal of cellular physiology 109 17154364
2010 TRPV2 channel negatively controls glioma cell proliferation and resistance to Fas-induced apoptosis in ERK-dependent manner. Carcinogenesis 93 20093382
2010 Ca2+-dependent desensitization of TRPV2 channels is mediated by hydrolysis of phosphatidylinositol 4,5-bisphosphate. The Journal of neuroscience : the official journal of the Society for Neuroscience 92 20926660
2005 Peripheral inflammation induces up-regulation of TRPV2 expression in rat DRG. Pain 79 16298071
2010 Involvement of TRPV2 activation in intestinal movement through nitric oxide production in mice. The Journal of neuroscience : the official journal of the Society for Neuroscience 78 21147993
2018 Conformational plasticity in the selectivity filter of the TRPV2 ion channel. Nature structural & molecular biology 77 29728656
2016 Lack of TRPV2 impairs thermogenesis in mouse brown adipose tissue. EMBO reports 74 26882545
2011 Differential TRPV1 and TRPV2 channel expression in dental pulp. Journal of dental research 74 21406609
2006 PI3-kinase promotes TRPV2 activity independently of channel translocation to the plasma membrane. Cell calcium 73 16533525
2004 Immunoreactive TRPV-2 (VRL-1), a capsaicin receptor homolog, in the spinal cord of the rat. The Journal of comparative neurology 72 14961565
2019 Oxidation of methionine residues activates the high-threshold heat-sensitive ion channel TRPV2. Proceedings of the National Academy of Sciences of the United States of America 71 31719194
2013 Blockade of sarcolemmal TRPV2 accumulation inhibits progression of dilated cardiomyopathy. Cardiovascular research 71 23786999
2020 TRPV2: A Cancer Biomarker and Potential Therapeutic Target. Disease markers 68 33376561
2016 Physiological significance of TRPV2 as a mechanosensor, thermosensor and lipid sensor. The journal of physiological sciences : JPS 67 26841959
2018 Phagocytosis depends on TRPV2-mediated calcium influx and requires TRPV2 in lipids rafts: alteration in macrophages from patients with cystic fibrosis. Scientific reports 65 29523858
2016 TRPV2 is a novel biomarker and therapeutic target in triple negative breast cancer. Oncotarget 65 30323891
2012 Expression and distribution of TRPV2 in rat brain. Experimental neurology 63 22750329
2007 2-Aminoethoxydiphenyl borate as a common activator of TRPV1, TRPV2, and TRPV3 channels. Handbook of experimental pharmacology 61 17217057
2001 Vanilloid receptor homologue, VRL1, is expressed by both A- and C-fiber sensory neurons. Neuroreport 61 11726776
2019 Cannabidiol Increases Proliferation, Migration, Tubulogenesis, and Integrity of Human Brain Endothelial Cells through TRPV2 Activation. Molecular pharmaceutics 59 30721081
2002 VRl- and VRL-l-like immunoreactivity in normal and injured trigeminal dental primary sensory neurons of the rat. Acta odontologica Scandinavica 59 12020118
2010 RANKL-induced TRPV2 expression regulates osteoclastogenesis via calcium oscillations. Cell calcium 58 20980052
2015 Dystrophic cardiomyopathy: role of TRPV2 channels in stretch-induced cell damage. Cardiovascular research 56 25616416
2010 Insulin/phosphoinositide 3-kinase pathway accelerates the glucose-induced first-phase insulin secretion through TrpV2 recruitment in pancreatic β-cells. The Biochemical journal 56 20854263
2022 Structural insights into TRPV2 activation by small molecules. Nature communications 54 35484159
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2013 Astrocytes express functional TRPV2 ion channels. Biochemical and biophysical research communications 50 24161738
2004 VR1-, VRL-1- and P2X3 receptor-immunoreactive innervation of the rat temporomandibular joint. Brain research 50 15081392
2004 Discrete expression of TRPV2 within the hypothalamo-neurohypophysial system: Implications for regulatory activity within the hypothalamic-pituitary-adrenal axis. The Journal of comparative neurology 50 15156577
2018 Structures of TRPV2 in distinct conformations provide insight into role of the pore turret. Nature structural & molecular biology 49 30598551
2016 Use Dependence of Heat Sensitivity of Vanilloid Receptor TRPV2. Biophysical journal 49 27074678
2021 Allosteric Antagonist Modulation of TRPV2 by Piperlongumine Impairs Glioblastoma Progression. ACS central science 48 34079902
2014 Loss of TRPV2 Homeostatic Control of Cell Proliferation Drives Tumor Progression. Cells 48 24709905
2003 The co-expression of VR1 and VRL-1 in the rat vagal sensory ganglia. Brain research 48 12867271
2017 Esophageal cancer stem cells are suppressed by tranilast, a TRPV2 channel inhibitor. Journal of gastroenterology 47 28389731
2016 TRPV2 Channels Contribute to Stretch-Activated Cation Currents and Myogenic Constriction in Retinal Arterioles. Investigative ophthalmology & visual science 45 27784066
2009 Ontogenetic expression of the vanilloid receptors TRPV1 and TRPV2 in the rat retina. International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience 43 19619635
2004 The co-expression of P2X3 receptor with VR1 and VRL-1 in the rat trigeminal ganglion. Brain research 43 14725976
2016 Activation of TRPV2 and BKCa channels by the LL-37 enantiomers stimulates calcium entry and migration of cancer cells. Oncotarget 42 26993604
2014 Mechanosensitive Ca²⁺-permeable channels in human leukemic cells: pharmacological and molecular evidence for TRPV2. Biochimica et biophysica acta 42 25268680
2013 Targeting TRPV1 and TRPV2 for potential therapeutic interventions in cardiovascular disease. Translational research : the journal of laboratory and clinical medicine 42 23453732
2005 TRPV2, a capsaicin receptor homologue, is expressed predominantly in the neurotrophin-3-dependent subpopulation of primary sensory neurons. Neuroscience 42 15561438
2022 Cannabidiol Inhibits Tumorigenesis in Cisplatin-Resistant Non-Small Cell Lung Cancer via TRPV2. Cancers 41 35267489
2022 Allosteric activation of the metabolic enzyme GPD1 inhibits bladder cancer growth via the lysoPC-PAFR-TRPV2 axis. Journal of hematology & oncology 41 35836291
2023 Cytosolic DNA sensing by cGAS/STING promotes TRPV2-mediated Ca2+ release to protect stressed replication forks. Molecular cell 39 36696898
2019 The expression and role of TRPV2 in esophageal squamous cell carcinoma. Scientific reports 39 31690728
2019 Symmetry transitions during gating of the TRPV2 ion channel in lipid membranes. eLife 38 31090543
2018 TRPV2 is required for mechanical nociception and the stretch-evoked response of primary sensory neurons. Scientific reports 38 30429536
2013 Involvement of TRPV2 and SOCE in calcium influx disorder in DMD primary human myotubes with a specific contribution of α1-syntrophin and PLC/PKC in SOCE regulation. American journal of physiology. Cell physiology 37 23426965
2012 Translocation of calcium-permeable TRPV2 channel to the podosome: Its role in the regulation of podosome assembly. Cell calcium 36 22226146
2005 The temperature-sensitive ion channel TRPV2 is endogenously expressed and functional in the primary sensory cell line F-11. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 35 15665528
2022 Structural mechanisms of TRPV2 modulation by endogenous and exogenous ligands. Nature chemical biology 34 36163384
2010 Characterization of calmodulin binding domains in TRPV2 and TRPV5 C-tails. Amino acids 34 20686800
2016 Activation of TRPV2 negatively regulates the differentiation of mouse brown adipocytes. Pflugers Archiv : European journal of physiology 33 27318696
2019 Mechanism for Regulation of Melanoma Cell Death via Activation of Thermo-TRPV4 and TRPV2. Journal of oncology 31 30881453
2004 Vanilloid receptor like 1 (VRL1) immunoreactivity in mammalian retina: colocalization with somatostatin and purinergic P2X1 receptors. The Journal of comparative neurology 31 15174083
2019 TRPV2 channels mediate insulin secretion induced by cell swelling in mouse pancreatic β-cells. American journal of physiology. Cell physiology 30 30649920
2013 The distribution of TRPV1 and TRPV2 in the rat pharynx. Cellular and molecular neurobiology 30 23584686
2003 Dual expression of mouse and rat VRL-1 in the dorsal root ganglion derived cell line F-11 and biochemical analysis of VRL-1 after heterologous expression. European journal of biochemistry 30 14622291
2017 Lysophosphatidylinositol-induced activation of the cation channel TRPV2 triggers glucagon-like peptide-1 secretion in enteroendocrine L cells. The Journal of biological chemistry 29 28533434
2015 Translocation of TRPV2 channel induced by focal administration of mechanical stress. Physiological reports 29 25677550
2007 Distribution of TRPV1- and TRPV2-immunoreactive afferent nerve endings in rat trachea. Journal of anatomy 28 17979952
1995 Delineation of the virulence-related locus (vrl) of Dichelobacter nodosus. Microbiology (Reading, England) 28 7496519
2013 Understanding the cellular function of TRPV2 channel through generation of specific monoclonal antibodies. PloS one 27 24392006
2023 Cannabidiol sensitizes TRPV2 channels to activation by 2-APB. eLife 26 37199723
2018 TRPV2 channel inhibitors attenuate fibroblast differentiation and contraction mediated by keratinocyte-derived TGF-β1 in an in vitro wound healing model of rats. Journal of dermatological science 26 29610016
2015 Novel role of TRPV2 in promoting the cytotoxicity of H2O2-mediated oxidative stress in human hepatoma cells. Free radical biology & medicine 26 26456053
2022 The effects of cannabidiol via TRPV2 channel in chronic myeloid leukemia cells and its combination with imatinib. Cancer science 25 34971020
2022 Tyrosine phosphorylation tunes chemical and thermal sensitivity of TRPV2 ion channel. eLife 25 35686730
2022 The Transient Receptor Potential Vanilloid 2 (TRPV2) Channel Facilitates Virus Infection Through the Ca2+ -LRMDA Axis in Myeloid Cells. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 24 36261399
2021 Tetrandrine Ameliorates Myocardial Ischemia Reperfusion Injury through miR-202-5p/TRPV2. BioMed research international 24 33763489
2020 Amelioration of diabetes-induced cognitive impairment by Transient Receptor Potential Vanilloid 2 (TRPV2) channel inhibitor: Behavioral and mechanistic study. Neurochemistry international 24 32652268
2019 TRPV2 suppresses Rac1 and RhoA activation and invasion in rheumatoid arthritis fibroblast-like synoviocytes. International immunopharmacology 24 30851707
2019 Blockade of TRPV2 is a Novel Therapy for Cardiomyopathy in Muscular Dystrophy. International journal of molecular sciences 24 31394715
2017 Marine Cyclic Guanidine Alkaloids Monanchomycalin B and Urupocidin A Act as Inhibitors of TRPV1, TRPV2 and TRPV3, but not TRPA1 Receptors. Marine drugs 24 28333079
2017 Stretch-activated TRPV2 channels: Role in mediating cardiopathies. Progress in biophysics and molecular biology 24 28546113
2023 The mechanosensitive TRPV2 calcium channel promotes human melanoma invasiveness and metastatic potential. EMBO reports 23 36744297
2021 Tranilast, a Transient Receptor Potential Vanilloid 2 Channel (TRPV2) Inhibitor Attenuates Amyloid β-Induced Cognitive Impairment: Possible Mechanisms. Neuromolecular medicine 23 34231190
2019 Evaluation of cationic channel TRPV2 as a novel biomarker and therapeutic target in Leukemia-Implications concerning the resolution of pulmonary inflammation. Scientific reports 23 30733502
1999 Complete nucleotide sequence of the 27-kilobase virulence related locus (vrl) of Dichelobacter nodosus: evidence for extrachromosomal origin. Infection and immunity 23 10024571
2019 Potential roles in cardiac physiology and pathology of the cation channel TRPV2 expressed in cardiac cells and cardiac macrophages: a mini-review. American journal of physiology. Heart and circulatory physiology 22 31809212
2016 Polymorphisms of the TRPV2 and TRPV3 genes associated with fibromyalgia in a Korean population. Rheumatology (Oxford, England) 22 27079220
2023 Pharmacological inhibition of TRPV2 attenuates phagocytosis and lipopolysaccharide-induced migration of primary macrophages. British journal of pharmacology 21 37254803
2022 The Protective Effect of CBD in a Model of In Vitro Ischemia May Be Mediated by Agonism on TRPV2 Channel and Microglia Activation. International journal of molecular sciences 21 36292998