{"gene":"TRPV2","run_date":"2026-06-10T10:51:56","timeline":{"discoveries":[{"year":2016,"finding":"Cryo-EM structure of rabbit TRPV2 at ~4 Å resolution reveals that S6 adopts a conformation distinct from TRPV1, and that rotation of the ankyrin-repeat domain is coupled to pore opening via the TRP domain; rearrangements in S6 secondary structure modulate pore opening.","method":"Cryo-electron microscopy (cryo-EM) structural determination at ~4 Å resolution","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — atomic-resolution cryo-EM structure with direct structural comparison to TRPV1, identifying specific gating mechanism","pmids":["26779611"],"is_preprint":false},{"year":2016,"finding":"Full-length TRPV2 cryo-EM structure at ~5 Å shows two constrictions (upper and lower gates), with wider upper and lower gates compared to closed and agonist-activated TRPV1, suggesting structural diversity among TRPV channels contributes to functional divergence.","method":"Cryo-electron microscopy (cryo-EM) of full-length TRPV2","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — full-length cryo-EM structure with direct structural comparison providing mechanistic insight into gating","pmids":["27021073"],"is_preprint":false},{"year":2019,"finding":"CBD binds TRPV2 through a hydrophobic pocket between S5 and S6 helices of adjacent subunits, a site distinct from known ligand/lipid sites in other TRP channels; the S4-S5 linker plays a critical role in channel gating upon CBD binding. Two distinct TRPV2 apo states were visualized in a lipid environment.","method":"Cryo-EM of full-length rat TRPV2 in nanodiscs in apo and CBD-bound states","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structures of multiple states with identified binding site and gating mechanism","pmids":["31566564"],"is_preprint":false},{"year":2018,"finding":"Crystal structures of rabbit TRPV2 in Ca2+-bound and resiniferatoxin (RTx)+Ca2+-bound forms reveal that RTx binding leads to two-fold symmetric opening of the selectivity filter wide enough for large organic cation permeation, establishing a structural basis for dual Ca2+ and large organic cation permeation.","method":"X-ray crystallography at 3.9 Å (Ca2+-bound) and 3.1 Å (RTx+Ca2+-bound) with functional electrophysiological characterization","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structures combined with functional characterization, multiple orthogonal methods","pmids":["29728656"],"is_preprint":false},{"year":2018,"finding":"Cryo-EM structures of rat TRPV2 reveal fully open and partially open states and resolve the full-length pore turret; activity assays demonstrate the pore turret is important for channel function, and structural data suggest lipid binding at the vanilloid pocket can regulate the lower gate and couple to the upper gate through a pore-turret-facilitated mechanism.","method":"Cryo-EM at 4.0 Å and 3.6 Å resolution combined with channel activity assays","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structures at multiple resolutions combined with functional assays","pmids":["30598551"],"is_preprint":false},{"year":2019,"finding":"RTx induces two-fold symmetric conformations of TRPV2 in both nanodisc and amphipol environments (more pronounced in nanodiscs), establishing that symmetry transitions during gating are an intrinsic property of TRPV2 and not solely due to crystal packing.","method":"Cryo-EM of full-length rabbit TRPV2 in complex with RTx in nanodiscs and amphipol","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM in two distinct environments with replicated finding of symmetry transition","pmids":["31090543"],"is_preprint":false},{"year":2022,"finding":"Cryo-EM structures of rat TRPV2 in lipid nanodiscs activated by 2-APB identify a TRPV2-specific binding site at the interface of S5 of one monomer and the S4-S5 linker of the adjacent monomer; His521 and Rac539 are key residues for 2-APB activation confirmed by mutagenesis and electrophysiology. Simultaneous binding of 2-APB and CBD was demonstrated structurally.","method":"Cryo-EM in lipid nanodiscs, in silico docking, electrophysiological studies, mutagenesis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure with mutagenesis validation and electrophysiology, multiple orthogonal methods","pmids":["35484159"],"is_preprint":false},{"year":2022,"finding":"Cryo-EM structures at 2.8–3.3 Å reveal an endogenous cholesterol molecule inside the vanilloid binding pocket (VBP) of TRPV2 with 'head down, tail up' configuration that antagonizes ligand activation; methyl-β-cyclodextrin removes cholesterol from VBP; estradiol potentiates 2-APB activation by disturbing cholesterol binding; 2-APB binds within the VBP.","method":"Cryo-EM at 2.8–3.3 Å resolution; pharmacological assays","journal":"Nature chemical biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution cryo-EM structures of multiple states with functional validation","pmids":["36163384"],"is_preprint":false},{"year":2023,"finding":"CBD sensitizes TRPV2 current responses to 2-APB by over two orders of magnitude without sensitizing to heat; cryo-EM reveals a new small-molecule binding site in the pore domain in addition to the previously reported CBD site. Strong sensitization by CBD is specific to TRPV2 (and TRPV3) and not transferred to TRPV1 by mutations at the CBD binding site or pore domain.","method":"Patch-clamp electrophysiology, cryo-EM, mutagenesis","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure combined with electrophysiology and mutagenesis, multiple orthogonal methods","pmids":["37199723"],"is_preprint":false},{"year":2010,"finding":"TRPV2 Ca2+-dependent desensitization is mediated by hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2), not calmodulin; simultaneous confocal imaging and electrophysiology showed TRPV2 desensitization was concomitant with PIP2 depletion. Calmodulin inhibitors and mutant calmodulin did not alter desensitization.","method":"Whole-cell patch-clamp, simultaneous confocal imaging with fluorescent PIP2-binding probe, calmodulin inhibitors, mutant calmodulin co-expression","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — multiple orthogonal methods (electrophysiology, live imaging, pharmacology, molecular tools) in single study","pmids":["20926660"],"is_preprint":false},{"year":2019,"finding":"Oxidation of methionine residues M528 and M607 activates and sensitizes TRPV2 to heat; chloramine-T, UVA light, and ROS-producing photosensitizers activate TRPV2 in excised inside-out patches (direct channel effect); DTT plus methionine sulfoxide reductase partially reverses activation; mass spectrometry confirms oxidation of these residues; macrophage phagocytosis is reduced by TRPV2 inhibitor or DTT.","method":"Electrophysiology (whole-cell and excised inside-out patches), site-directed mutagenesis (M528I, M607I), mass spectrometry on purified TRPV2 protein, pharmacological assays in macrophages","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with mutagenesis and MS validation, multiple orthogonal methods","pmids":["31719194"],"is_preprint":false},{"year":2022,"finding":"JAK1 mediates TRPV2 tyrosine phosphorylation at Tyr335, Tyr471, and Tyr525; enhanced tyrosine phosphorylation alters chemical and thermal sensitivity of TRPV2 in macrophages and DRG neurons; PTPN1 dephosphorylates TRPV2, dynamically balancing its activity; JAK1 phosphorylation is required for TRPV2 activity and macrophage phagocytic ability.","method":"Electrophysiology, site-directed mutagenesis, kinase/phosphatase assays, phagocytosis assays in macrophages and DRG neurons","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — identification of specific phosphorylation sites with writer (JAK1) and eraser (PTPN1) plus functional validation","pmids":["35686730"],"is_preprint":false},{"year":2010,"finding":"Calmodulin binds to the C-terminus of TRPV2 (residues 654–683) via a 1-5-10 consensus motif; R679A and K681A mutations reduce binding affinity by 50%, and double mutation K661A/K664A reduces affinity by 75%, identifying basic residues critical for calmodulin interaction.","method":"In vitro calmodulin binding assays with peptides, site-directed mutagenesis","journal":"Amino acids","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro peptide binding with mutagenesis, single lab, peptide-based (not full channel)","pmids":["20686800"],"is_preprint":false},{"year":2005,"finding":"TRPV1 and TRPV2 form heteromeric complexes, as demonstrated by co-immunoprecipitation from HEK cells, F-11 cells, and rat DRG lysates; a small population of native DRG neurons co-expresses both channels at the cell surface.","method":"Co-immunoprecipitation from transfected mammalian cells and native rat DRG; immunofluorescence co-localization","journal":"Neuroreport","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — reciprocal co-IP in both heterologous and native cells, confirmed by immunofluorescence","pmids":["16237318"],"is_preprint":false},{"year":2004,"finding":"TRPV2 forms a complex with PKA and the A-kinase adapter protein ACBD3 in mast cells; TRPV2 is surface-localized and functionally coupled to Ca2+ fluxes and degranulation; cAMP/PKA-dependent regulated phosphorylation is proposed as a modulation mechanism for TRPV2.","method":"Co-immunoprecipitation, calcium flux assays, degranulation assays, surface localization by immunostaining in mast cells","journal":"The Journal of experimental medicine","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP identifying PKA-ACBD3-TRPV2 complex with functional Ca2+ and degranulation readouts, single lab","pmids":["15249591"],"is_preprint":false},{"year":2005,"finding":"RGA protein forms a physiological complex with TRPV2 in mast cells; overexpression of RGA potentiates basal surface localization of TRPV2; elevations in cytosolic cAMP drive plasma membrane localization of TRPV2 in mast cells.","method":"Co-immunoprecipitation with polyclonal anti-RGA antibody, flow cytometry for surface TRPV2 quantification, overexpression studies","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP confirming physiological complex, surface expression quantification, single lab","pmids":["15547947"],"is_preprint":false},{"year":2008,"finding":"In pancreatic beta-cells, insulin induces translocation of TRPV2 from cytoplasm to the plasma membrane via the insulin receptor/PI3K pathway; this translocation increases Ca2+ entry and is required for autocrine insulin secretion stimulated by glucose; knockdown of TRPV2 or insulin receptor attenuates these effects.","method":"GFP-TRPV2 live-cell imaging, Myc-tagged TRPV2 surface detection, fura-2 Ca2+ imaging, shRNA knockdown, insulin receptor knockout beta-cells","journal":"Diabetes","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (live imaging, Ca2+ imaging, shRNA KD, receptor KO), replicated in primary beta-cells and cell lines","pmids":["18984736"],"is_preprint":false},{"year":2010,"finding":"Insulin/PI3K signaling accelerates glucose-induced first-phase insulin secretion by recruiting TRPV2 to the plasma membrane in beta-cells; PI3K inhibition abolishes insulin-induced rapid exocytotic response; TRPV2 inhibition (tranilast) or shRNA suppresses first-phase but not second-phase insulin secretion.","method":"Total internal reflection fluorescent microscopy (TIRFM) for exocytosis, Ca2+ imaging, PI3K inhibition, tranilast pharmacology, shRNA knockdown","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 2 / Moderate — TIRFM exocytosis imaging combined with pharmacology and shRNA, multiple orthogonal methods","pmids":["20854263"],"is_preprint":false},{"year":2006,"finding":"PI3K promotes TRPV2 channel activity independently of channel translocation to the plasma membrane; cytotoxicity (a read-out of channel activity) is prevented by a pore-domain charge substitution or reduced extracellular Ca2+; PI3K inhibition decreases TRPV2 activity without affecting plasma membrane trafficking.","method":"Cytotoxicity assays, stable transfection electrophysiology, direct measurement of cell surface TRPV2 expression, pore-domain mutagenesis","journal":"Cell calcium","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cytotoxicity and surface expression assays with mutagenesis, challenges prior trafficking model","pmids":["16533525"],"is_preprint":false},{"year":2009,"finding":"Lysophospholipids (LPC and LPI) activate TRPV2 via Gq/Go-protein and PI3,4-kinase signaling, causing TRPV2 translocation to the plasma membrane, Ca2+ influx, and increased prostate cancer cell migration; activation depends on lysophospholipid side-chain length and head-group nature.","method":"Ca2+ imaging, TRPV2 translocation assays, migration assays, pharmacological signaling pathway dissection in PC3 cells","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — multiple assays (Ca2+ imaging, translocation, migration) with pharmacological pathway dissection, single lab","pmids":["19321128"],"is_preprint":false},{"year":2013,"finding":"Adrenomedullin induces prostate and urothelial cancer cell migration and invasion through TRPV2 translocation to the plasma membrane and subsequent increase in resting calcium levels.","method":"TRPV2 translocation assays, Ca2+ imaging, migration and invasion assays in cancer cell lines","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — translocation and Ca2+ imaging with migration assays, single lab","pmids":["23741410"],"is_preprint":false},{"year":2015,"finding":"Focal mechanical stress applied to HT1080 cells causes TRPV2 translocation to the site of stress in a PI3K/Rac1-dependent manner and increases sub-plasma membrane Ca2+ concentration; this Ca2+ elevation requires extracellular Ca2+ and TRPV2, as demonstrated by ruthenium red inhibition and TRPV2 knockdown.","method":"Live GFP-TRPV2 and RFP-Akt imaging, mechanical stress application by glass pipette, ruthenium red pharmacology, TRPV2 siRNA knockdown, dominant-negative Rac","journal":"Physiological reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — live imaging with siRNA and pharmacological validation, PI3K/Rac pathway dissection","pmids":["25677550"],"is_preprint":false},{"year":2014,"finding":"TRPV2 is critical for maintenance of cardiac structure and function; conditional cardiac-specific elimination of TRPV2 causes disorganization of intercalated discs, myocardial conduction defects, impaired Ca2+ handling, and reduced IGF-1 secretion in response to stretch; IGF-1 receptor/PI3K/Akt signaling is significantly downregulated in TRPV2-deficient hearts; IGF-1 administration partially rescues cardiomyopathy.","method":"Conditional TRPV2 knockout in adult mice, echocardiography, single cardiomyocyte Ca2+ handling, neonatal cardiomyocyte stretch experiments, Western blotting, IGF-1 rescue experiments","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with multiple functional readouts and pathway rescue, replicated across developmental stages","pmids":["24874017"],"is_preprint":false},{"year":2013,"finding":"Sarcolemmal accumulation of TRPV2 is elevated in dilated cardiomyopathy (DCM) patients and three animal models; overexpression of TRPV2 N-terminal domain blocks plasma membrane accumulation and Ca2+ influx, reduces CaMKII phosphorylation and ROS production, prevents ventricular dilation and fibrosis, and improves survival; TRPV2 inhibitor tranilast suppresses DCM progression.","method":"Immunological analyses, transgenic/adenoviral N-terminal domain overexpression in DCM animals, Western blotting, echocardiography, survival analysis, tranilast pharmacology","journal":"Cardiovascular research","confidence":"High","confidence_rationale":"Tier 2 / Strong — gain-of-function and loss-of-function in multiple animal models with mechanistic downstream pathway characterization","pmids":["23786999"],"is_preprint":false},{"year":2015,"finding":"In dystrophic (mdx) cardiomyocytes, TRPV2 is overexpressed and translocated from intracellular compartments to the sarcolemma and T-tubules; pharmacological inhibition, pore-blocking antibodies, and siRNA ablation of TRPV2 protect mdx cells from stretch-induced abnormal Ca2+ signals, establishing TRPV2 as a stretch-activated Ca2+ influx channel in dystrophic cardiomyopathy.","method":"Western blotting, immunocytochemistry, biotinylation assays, patch-clamp pharmacology, confocal Ca2+ imaging, pore-blocking antibodies, siRNA knockdown","journal":"Cardiovascular research","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (biochemical, imaging, antibody blocking, siRNA) establishing TRPV2 in stretch-activated Ca2+ pathway","pmids":["25616416"],"is_preprint":false},{"year":2016,"finding":"TRPV2 knockout mice have reduced thermogenic gene expression in brown adipose tissue in response to β-adrenergic receptor stimulation, increased body weight and fat, and cold intolerance, indicating TRPV2 plays a role in BAT thermogenesis; Ca2+ influx via TRPV2 is required for thermogenic gene induction.","method":"TRPV2 KO mice, gene expression analysis, β-adrenergic stimulation experiments, intracellular Ca2+ manipulation","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse with Ca2+ manipulation and gene expression readouts, single lab","pmids":["26882545"],"is_preprint":false},{"year":2010,"finding":"TRPV2 activation inhibits spontaneous intestinal circular muscle contraction through nitric oxide (NO) production; mechanical stimuli activate TRPV2-like inward currents in myenteric neurons (inhibited by tranilast); TRPV2 agonists increase intestinal NO production and accelerate gastrointestinal transit in vivo.","method":"Dissociated myenteric neuron patch-clamp, isolated intestine contraction assays, NO synthase pathway inhibitors, Ca2+ imaging, in vivo gastrointestinal transit assay","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — patch-clamp, pharmacology, ex vivo and in vivo assays establishing TRPV2→NO→motility pathway","pmids":["21147993"],"is_preprint":false},{"year":2016,"finding":"TRPV2 contributes to stretch-activated cation currents and myogenic constriction in retinal arterioles; hypoosmotic stretch-induced Ca2+ influx in retinal VSMCs is blocked by tranilast and TRPV2 pore-blocking antibodies; preincubation with TRPV2 blocking antibodies prevents development of myogenic tone.","method":"Patch-clamp electrophysiology, Fura-2 Ca2+ microfluorimetry, pressure myography, TRPV2 pore-blocking antibodies, tranilast pharmacology","journal":"Investigative ophthalmology & visual science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple electrophysiological and pharmacological methods with specific pore-blocking antibodies","pmids":["27784066"],"is_preprint":false},{"year":2010,"finding":"RANKL upregulates TRPV2 expression in preosteoclasts and drives spontaneous Ca2+ oscillations and transient inward cation currents; TRPV2 silencing reduces Ca2+ oscillation frequency and current amplitude, decreases NFATc1 expression and nuclear translocation, and inhibits osteoclastogenesis.","method":"DNA microarray, siRNA silencing of TRPV2, Ca2+ imaging, patch-clamp, Western blotting for NFATc1","journal":"Cell calcium","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA with Ca2+ imaging and electrophysiology identifying RANKL→TRPV2→NFATc1 pathway, single lab","pmids":["20980052"],"is_preprint":false},{"year":2018,"finding":"TRPV2 in Ca2+-calcineurin-NFAT signaling regulates RANKL-dependent osteoclastic differentiation in multiple myeloma; TRPV2 gates Ca2+ influx in MM cells in high Ca2+ environment; SKF96365 inhibition of TRPV2 attenuates osteoclast formation in vitro.","method":"Fluo-4 Ca2+ staining, Western blotting, ChIP assays, ELISA, TRAP staining, TRPV2 inhibitor","journal":"Cell communication and signaling","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — multiple biochemical assays with pharmacological inhibition establishing pathway","pmids":["30326911"],"is_preprint":false},{"year":2023,"finding":"Replication stress causes ssDNA/dsDNA to translocate to the cytoplasm, activating cGAS and producing cGAMP; cGAMP binding to STING causes its dissociation from TRPV2, derepressing TRPV2 and causing Ca2+ release from the ER, which activates CaMKK2/AMPK to protect replication forks from Exo1-mediated degradation.","method":"Genetic manipulation, biochemical co-immunoprecipitation (STING-TRPV2 interaction), Ca2+ measurements, epistasis analysis","journal":"Molecular cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP of STING-TRPV2 interaction with functional pathway epistasis, single lab","pmids":["36696898"],"is_preprint":false},{"year":2022,"finding":"TRPV2 in myeloid cells facilitates virus penetration by promoting cell membrane tension and mobility through the Ca2+-LRMDA axis; Ca2+-impermeable TRPV2-E572Q mutant fails to restore viral infection in TRPV2 KO cells; TRPV2 KO leads to downregulation of Lrmda and reduced membrane tension; LRMDA complementation restores membrane tension and viral penetration.","method":"TRPV2 conditional KO, reconstitution with TRPV2 or Ca2+-impermeable mutant, LRMDA knockdown/complementation, membrane tension and mobility assays","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic reconstitution with Ca2+-impermeable mutant and downstream LRMDA axis characterization","pmids":["36261399"],"is_preprint":false},{"year":2018,"finding":"Phagocytosis in primary human macrophages requires TRPV2-mediated Ca2+ influx; P. aeruginosa recruits TRPV2 to the cell surface; TRPV2 must be localized in lipid rafts to be functional for phagocytosis; CF macrophages display deficient TRPV2 function and impaired phagocytosis.","method":"Pharmacological inhibition of TRPV2, siRNA knockdown, phagocytosis assays, Ca2+ imaging, lipid raft fractionation","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple methods including lipid raft fractionation and siRNA in primary human macrophages","pmids":["29523858"],"is_preprint":false},{"year":2024,"finding":"TRPV2 is highly expressed in B cells and required for B cell immunological synapse formation and activation; the pore and N-terminal domains are critical for cation permeation and mechanosensation; TRPV2 deficiency in B cells impairs antibody responses; TRPV2 activity promotes membrane potential depolarization and cytoskeleton remodeling during antigen stimulation.","method":"B cell-specific TRPV2 KO mice, immunological synapse imaging, antibody response assays, domain-specific mutagenesis","journal":"The Journal of experimental medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — B cell-specific KO with mechanistic domain analysis and functional immune readouts, single lab","pmids":["38353705"],"is_preprint":false},{"year":2019,"finding":"TRPV2 silencing increases glioma (U87MG) cell proliferation, rescues cells from Fas-induced apoptosis, downregulates Fas and procaspase-8 expression, and upregulates Bcl-XL; these effects depend on ERK activation; ERK inhibition (PD98059) restores Akt/PKB activation, reduces Bcl-XL, promotes Fas expression, and increases apoptosis sensitivity in TRPV2-silenced cells.","method":"siRNA silencing, RT-Profiler PCR array, BrdU proliferation assay, flow cytometry apoptosis, ERK inhibitor PD98059","journal":"Carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — siRNA with multiple downstream molecular readouts and pharmacological pathway validation","pmids":["20093382"],"is_preprint":false},{"year":2023,"finding":"TRPV2 localizes at the leading edge in dynamic nascent adhesions of invasive melanoma cells; TRPV2 activity regulates calcium-mediated activation of calpain and cleavage of talin, along with F-actin organization; TRPV2 silencing prevents aggressive migratory and invasive behavior; TRPV2 activity is sufficient to confer migratory and invasive potential.","method":"In vitro migration/invasion assays, in vivo mouse models, TRPV2 silencing, live-cell imaging of TRPV2 localization, calpain activity assays, talin cleavage Western blot, F-actin staining","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo assays with mechanistic calpain/talin pathway characterization and TRPV2 localization, single lab","pmids":["36744297"],"is_preprint":false},{"year":2019,"finding":"TRPV2 stimulation in rheumatoid arthritis fibroblast-like synoviocytes reduces FLS adhesion, decreases integrin (αν, β1, β3) localization to plasma membrane, reduces activated RhoA and Rac1 levels, decreases cofilin activation, and inhibits invasion; RhoA activators overcome TRPV2-induced suppression.","method":"TRPV2 pharmacological stimulation, FLS adhesion and invasion assays, integrin surface localization, RhoA/Rac1 activity assays, cofilin western blotting","journal":"International immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — pharmacological TRPV2 stimulation with multiple downstream signaling readouts, single lab","pmids":["30851707"],"is_preprint":false},{"year":2016,"finding":"LL-37 activates TRPV2 and recruits it to pseudopodia via PI3K/AKT pathway activation, causing Ca2+ entry that cooperates with BKCa channel K+ efflux to drive cancer cell migration; LL-37 D-enantiomer has identical effects, suggesting membrane physical property modification rather than specific receptor binding is the mechanism.","method":"Ca2+ imaging, migration assays (wound healing), PI3K/AKT inhibition, D-enantiomer controls, confocal microscopy of TRPV2 localization","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Ca2+ imaging and migration assays with D-enantiomer mechanistic control and PI3K/AKT pathway validation","pmids":["26993604"],"is_preprint":false},{"year":2016,"finding":"Heat sensitivity of TRPV2 exhibits strong use dependence: prior heat activation decreases activation temperature threshold, reduces slope sensitivity, and accelerates activation time courses. Prior heat sensitizes agonist responses, but agonist activation does not sensitize heat responses (non-reciprocal cross-use-dependence), indicating separate temperature sensing and agonist activation pathways.","method":"Electrophysiology (patch-clamp), quantitative thermal activation analysis","journal":"Biophysical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — rigorous quantitative electrophysiology establishing use-dependence mechanism, single lab","pmids":["27074678"],"is_preprint":false},{"year":2019,"finding":"TRPV2 channels mediate osmotic cell swelling-induced insulin secretion in mouse beta-cells; TRPV2 siRNA knockdown and tranilast reduce hypotonic stimulation-induced Ca2+ elevation and insulin secretion; glucose-stimulated insulin secretion is also reduced by TRPV2 knockdown.","method":"Ca2+ imaging, siRNA knockdown, tranilast pharmacology, insulin secretion ELISA from isolated islets","journal":"American journal of physiology. Cell physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with Ca2+ imaging and functional insulin secretion assays","pmids":["30649920"],"is_preprint":false},{"year":2015,"finding":"TRPV2 dominant-negative expressing skeletal muscle fibres show slower membrane depolarization, diminished Ca2+ response, smaller regulatory volume increase (RVI), and decreased SPAK phosphorylation in response to hyperosmotic shock, suggesting TRPV2 activation depolarizes T-tubules, triggering Ca2+ release from sarcoplasmic reticulum and activating SPAK/NKCC1 for RVI.","method":"TRPV2 dominant-negative overexpression in skeletal muscle fibres, Ca2+ imaging, membrane potential measurements, SPAK phosphorylation Western blot, BAPTA chelation","journal":"The Journal of physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — dominant-negative model with multiple functional readouts and Ca2+ chelator controls","pmids":["26108786"],"is_preprint":false},{"year":2012,"finding":"In the retinal pigment epithelium, TRPV2 mediates the sustained Ca2+ elevation phase of angiotensin II signaling; TRPV2 siRNA reduces the sustained phase of AngII-mediated Ca2+ transients by 53%; TRPV2 co-localizes with AT1R/Atrap complex; IGF-1 and CBD increase TRPV2 surface expression via PI3K.","method":"siRNA knockdown, Ca2+ imaging, SKF96365 pharmacology, immunostaining, co-localization analysis","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — siRNA with pharmacology and Ca2+ imaging in primary porcine RPE cells","pmids":["23185387"],"is_preprint":false},{"year":2015,"finding":"In the retinal pigment epithelium, IGF-1 increases TRPV2 surface expression and channel activity via PI3K; CBD increases TRPV2 surface expression (more than IGF-1) and channel activity; PI3K inhibitor LY294002 abolishes both effects; heat further potentiates CBD- but not IGF-1-stimulated conductance.","method":"Whole-cell patch-clamp, confocal microscopy for surface TRPV2 quantification, PI3K inhibition, IGF-1 and CBD pharmacology in ARPE-19 cells","journal":"Graefe's archive for clinical and experimental ophthalmology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — patch-clamp with surface expression quantification and pharmacological dissection of PI3K pathway","pmids":["25616727"],"is_preprint":false},{"year":2003,"finding":"VRL-1 (TRPV2) expressed in F-11 cells is N-glycosylated when overexpressed heterologously, similar to VR1; endogenous VRL-1 in F-11 cells shows mainly cytoplasmic localization by immunofluorescence, whereas overexpressed rat VRL-1 appears mainly at the plasma membrane.","method":"RT-PCR, deglycosylation assay (N-linked glycosylation), immunofluorescence localization","journal":"European journal of biochemistry","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, biochemical characterization only, indirect localization readout","pmids":["14622291"],"is_preprint":false},{"year":2016,"finding":"TRPV2 activation inhibits differentiation of brown adipocytes in a dose-dependent manner during early differentiation stages via a calcineurin pathway; mechanical force also inhibits differentiation through TRPV2; these effects are significantly reduced in TRPV2 KO cells and reversed by calcineurin inhibitors (cyclosporine A, FK506).","method":"TRPV2 KO mouse adipocytes, TRPV2 agonist/antagonist pharmacology, mechanical stimulation, calcineurin inhibitors, differentiation markers","journal":"Pflugers Archiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO cells with pharmacological and mechanical stimulation establishing calcineurin pathway, single lab","pmids":["27318696"],"is_preprint":false}],"current_model":"TRPV2 is a Ca2+-permeable, non-selective cation channel that adopts a homotetrameric structure with two gates (upper/selectivity filter and lower/S6), is tonically retained in intracellular pools (ER) under basal conditions, and is activated by diverse stimuli including noxious heat (>52°C), mechanical/osmotic stress, lipids (lysophospholipids, cholesterol acts as an endogenous inhibitor in the vanilloid binding pocket), and small-molecule agonists (cannabidiol, 2-APB, probenecid, resiniferatoxin) that bind distinct sites in or near the S5/S6 transmembrane domain; channel gating involves ankyrin-repeat domain rotation coupled to the TRP domain and S6, symmetry transitions at the selectivity filter, and modulation by PIP2 hydrolysis (mediating Ca2+-dependent desensitization) and post-translational modifications including JAK1-mediated tyrosine phosphorylation (Tyr335/471/525, activating) and methionine oxidation (M528/M607, activating); plasma membrane translocation—triggered by PI3K, insulin, growth factors, cAMP/PKA, or mechanical stimuli—is a key regulatory mechanism controlling TRPV2 activity in non-neuronal cells, and TRPV2 engages downstream signaling cascades including Ca2+-calcineurin-NFAT (osteoclastogenesis), CaMKII, PI3K/Akt (cardiac function, cancer migration), RhoA/Rac1 (invasion), calpain/talin (leading edge dynamics), NO production (intestinal motility), and the cGAS/STING/TRPV2/CaMKK2/AMPK axis (replication fork protection), with established roles in cardiac mechanosensation, mast cell degranulation, macrophage phagocytosis, B cell activation, beta-cell insulin secretion, brown adipose thermogenesis, and cancer cell migration/invasion."},"narrative":{"mechanistic_narrative":"TRPV2 is a Ca2+-permeable, non-selective cation channel that functions as a polymodal sensor of heat, mechanical/osmotic stress, lipids, and small-molecule agonists, transducing these stimuli into Ca2+ signals that drive cytoskeletal remodeling, secretion, and gene expression across diverse non-neuronal cell types [PMID:29728656, PMID:18984736, PMID:36744297]. Structurally it is a homotetramer with an upper (selectivity filter) and lower (S6) gate, in which agonist (resiniferatoxin) binding drives a two-fold symmetric opening of the selectivity filter wide enough to permeate large organic cations, while rotation of the ankyrin-repeat domain couples through the TRP domain to S6 to open the pore [PMID:26779611, PMID:29728656, PMID:31090543]. Distinct ligand sites govern gating: cannabidiol binds a hydrophobic pocket between S5 and S6 of adjacent subunits acting through the S4-S5 linker, 2-APB binds a TRPV2-specific S5/S4-S5 interface site (His521/Arg539), and an endogenous cholesterol molecule occupies the vanilloid binding pocket as an inhibitor that is relieved by methyl-β-cyclodextrin or estradiol [PMID:31566564, PMID:35484159, PMID:36163384]. Channel activity is tuned post-translationally by Ca2+-dependent desensitization via PIP2 hydrolysis [PMID:20926660], methionine oxidation at M528/M607 (heat-sensitizing and required for macrophage phagocytosis) [PMID:31719194], and JAK1-mediated tyrosine phosphorylation at Tyr335/471/525 balanced by the phosphatase PTPN1 [PMID:35686730]. A central regulatory theme is stimulus-triggered translocation from intracellular pools to the plasma membrane, driven by insulin/PI3K, growth factors, lysophospholipids, adrenomedullin, mechanical stress, and cAMP, which controls Ca2+ entry in beta-cell insulin secretion, cancer cell migration, and cardiac mechanosensation [PMID:18984736, PMID:19321128, PMID:25677550, PMID:23786999]. Through this gating and trafficking, TRPV2 engages downstream Ca2+-calcineurin-NFAT signaling in osteoclastogenesis and brown adipocyte regulation [PMID:20980052, PMID:27318696], calpain/talin and RhoA/Rac1 cascades governing leading-edge dynamics and invasion [PMID:36744297, PMID:30851707], IGF-1/PI3K/Akt signaling sustaining cardiac structure and function [PMID:24874017, PMID:23786999], and a cytoplasmic cGAS/STING-derepressed Ca2+ release pathway that activates CaMKK2/AMPK to protect replication forks [PMID:36696898].","teleology":[{"year":2003,"claim":"Established the basic biochemical and localization properties of TRPV2, addressing whether the channel is processed and where it resides in cells.","evidence":"RT-PCR, N-glycosylation deglycosylation assays, and immunofluorescence in F-11 cells","pmids":["14622291"],"confidence":"Low","gaps":["Single lab, indirect localization readout","Overexpression artifact possible for plasma membrane signal","No functional channel measurement"]},{"year":2008,"claim":"Showed that stimulus-driven plasma membrane translocation, not just intrinsic gating, controls TRPV2 function, answering how an intracellular channel becomes active for physiological Ca2+ entry.","evidence":"GFP-TRPV2 imaging, surface detection, Ca2+ imaging, shRNA knockdown, and insulin receptor knockout in beta-cells (also #17, #19, #20, #21)","pmids":["18984736","20854263","19321128","23741410","25677550"],"confidence":"High","gaps":["Molecular machinery of vesicular trafficking not defined","Translocation vs. direct activity contributions not always separated","PI3K can promote activity independent of trafficking (#18), unresolved"]},{"year":2010,"claim":"Resolved the mechanism of Ca2+-dependent desensitization, distinguishing PIP2 hydrolysis from calmodulin as the negative regulator of the channel.","evidence":"Whole-cell patch-clamp with simultaneous confocal PIP2 probe imaging and calmodulin perturbation","pmids":["20926660"],"confidence":"High","gaps":["Calmodulin still binds the C-terminus (#12) with unclear functional role","Structural basis of PIP2 action not resolved","Lipid binding site not mapped in this study"]},{"year":2016,"claim":"Provided the first atomic-scale gating model by showing ankyrin-repeat domain rotation coupled through the TRP domain to S6, and defined two-gate architecture.","evidence":"Cryo-EM of rabbit and full-length TRPV2 (also #1)","pmids":["26779611","27021073"],"confidence":"High","gaps":["Resolution limited (~4-5 Å)","Ligand-bound and physiological lipid states not yet captured","Coupling of upper and lower gates incompletely defined"]},{"year":2018,"claim":"Defined the structural basis for dual Ca2+ and large organic cation permeation by showing agonist-induced two-fold symmetric selectivity filter opening, an intrinsic gating property.","evidence":"X-ray crystallography and cryo-EM with electrophysiology in Ca2+/RTx-bound states (also #4, #5)","pmids":["29728656","30598551","31090543"],"confidence":"High","gaps":["Physiological trigger of symmetry transition in vivo unclear","Pore turret role beyond functional importance not mechanistically dissected","Heat-induced conformations not captured"]},{"year":2019,"claim":"Mapped distinct small-molecule and lipid binding sites (CBD between S5/S6; later 2-APB at an S5/S4-S5 interface) and an endogenous cholesterol inhibitor in the vanilloid pocket, explaining polypharmacology and endogenous tone.","evidence":"Cryo-EM in nanodiscs with mutagenesis and electrophysiology (also #6, #7, #8)","pmids":["31566564","35484159","36163384","37199723"],"confidence":"High","gaps":["Endogenous heat-sensing site distinct from agonist sites (#38) not structurally resolved","Physiological regulation of cholesterol occupancy unknown","How CBD sensitization to 2-APB but not heat is encoded structurally not fully explained"]},{"year":2019,"claim":"Identified covalent activating modifications, establishing TRPV2 as an oxidation- and phosphorylation-gated channel with defined writers, erasers, and residues.","evidence":"Excised-patch electrophysiology, mutagenesis, mass spectrometry, and kinase/phosphatase assays (also #11)","pmids":["31719194","35686730"],"confidence":"High","gaps":["Physiological sources of oxidation in vivo not fully defined","Crosstalk between oxidation, phosphorylation, and lipid regulation unmapped","Structural consequences of modifications not visualized"]},{"year":2014,"claim":"Established TRPV2 as a cardiac mechanosensor required for structural integrity and Ca2+ handling, linking it to IGF-1/PI3K/Akt signaling and disease.","evidence":"Conditional cardiac KO with echocardiography, Ca2+ handling, stretch experiments, and IGF-1 rescue (also #23, #24)","pmids":["24874017","23786999","25616416"],"confidence":"High","gaps":["Direct stretch-sensing mechanism at molecular level not resolved","Relationship between sarcolemmal accumulation and pathology vs. protection context-dependent","No timeline evidence of a human Mendelian mutation"]},{"year":2018,"claim":"Connected TRPV2-mediated Ca2+ entry to effector pathways driving cell migration, invasion, and cytoskeletal remodeling in cancer and immune contexts.","evidence":"Silencing/pharmacology with calpain/talin, RhoA/Rac1, and ERK readouts and in vivo invasion models (also #34, #36, #37)","pmids":["36744297","20093382","30851707","26993604"],"confidence":"Medium","gaps":["Largely single-lab studies per cell type","Direct vs. indirect coupling to calpain/RhoA not fully established","Context-dependent pro- vs. anti-invasive effects unresolved"]},{"year":2018,"claim":"Demonstrated TRPV2's role in innate and adaptive immune cell function, including phagocytosis, viral penetration, and B cell synapse formation, via Ca2+ and membrane mechanics.","evidence":"siRNA/conditional KO, lipid raft fractionation, reconstitution with Ca2+-impermeable mutants, and functional immune assays (also #31, #33)","pmids":["29523858","36261399","38353705"],"confidence":"Medium","gaps":["Recruitment mechanism to phagocytic cup/synapse not fully defined","LRMDA axis mechanistic detail incomplete","Single-lab findings per immune cell type"]},{"year":2023,"claim":"Placed TRPV2 in a genome-stability pathway, showing STING dissociation derepresses TRPV2 to release ER Ca2+ and protect replication forks via CaMKK2/AMPK.","evidence":"STING-TRPV2 co-immunoprecipitation, Ca2+ measurements, and pathway epistasis","pmids":["36696898"],"confidence":"Medium","gaps":["Single Co-IP for STING-TRPV2 interaction without structural validation","ER-resident vs. plasma membrane pool contribution not separated","Generality across cell types untested"]},{"year":null,"claim":"How the structurally defined heat-sensing pathway, distinct agonist/lipid sites, and post-translational modifications integrate with stimulus-gated trafficking to set cell-type-specific TRPV2 output remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of a heat-activated state","Trafficking machinery and recruitment signals undefined","Integration of oxidation, phosphorylation, lipid, and PIP2 inputs not unified mechanistically"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[10,38]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[24,33]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[14,16,24,32]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[30]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[16,43]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[16,22,28,30]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[32,33,31]},{"term_id":"R-HSA-397014","term_label":"Muscle contraction","supporting_discovery_ids":[22,24,40]}],"complexes":[],"partners":["TRPV1","STING1","PRKACA","ACBD3","CALM1","PTPN1","JAK1","LRMDA"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9Y5S1","full_name":"Transient receptor potential cation channel subfamily V member 2","aliases":["Osm-9-like TRP channel 2","OTRPC2","Vanilloid receptor-like protein 1","VRL-1"],"length_aa":764,"mass_kda":86.0,"function":"Calcium-permeable, non-selective cation channel (PubMed:10201375). Seems to be regulated, at least in part, by growth factors, such as IGF1, PDGF and morphogenetic neuropeptide/head activator. May transduce physical stimuli in mast cells (By similarity)","subcellular_location":"Cell membrane; Cytoplasm; Melanosome","url":"https://www.uniprot.org/uniprotkb/Q9Y5S1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TRPV2","classification":"Not Classified","n_dependent_lines":18,"n_total_lines":1208,"dependency_fraction":0.014900662251655629},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TRPV2","total_profiled":1310},"omim":[{"mim_id":"606676","title":"TRANSIENT RECEPTOR POTENTIAL CATION CHANNEL, SUBFAMILY V, MEMBER 2; TRPV2","url":"https://www.omim.org/entry/606676"},{"mim_id":"605427","title":"TRANSIENT RECEPTOR POTENTIAL CATION CHANNEL, SUBFAMILY V, MEMBER 4; TRPV4","url":"https://www.omim.org/entry/605427"},{"mim_id":"310200","title":"MUSCULAR DYSTROPHY, DUCHENNE TYPE; DMD","url":"https://www.omim.org/entry/310200"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TRPV2"},"hgnc":{"alias_symbol":["VRL","VRL-1","VRL1"],"prev_symbol":[]},"alphafold":{"accession":"Q9Y5S1","domains":[{"cath_id":"1.25.40.20","chopping":"12-20_42-62_71-217","consensus_level":"medium","plddt":85.2575,"start":12,"end":217},{"cath_id":"1.25.40","chopping":"238-317","consensus_level":"medium","plddt":91.5899,"start":238,"end":317},{"cath_id":"-","chopping":"386-414_426-517","consensus_level":"medium","plddt":87.1475,"start":386,"end":517}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y5S1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y5S1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y5S1-F1-predicted_aligned_error_v6.png","plddt_mean":78.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TRPV2","jax_strain_url":"https://www.jax.org/strain/search?query=TRPV2"},"sequence":{"accession":"Q9Y5S1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y5S1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y5S1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y5S1"}},"corpus_meta":[{"pmid":"26779611","id":"PMC_26779611","title":"Cryo-electron 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rearrangements in S6 secondary structure modulate pore opening.\",\n      \"method\": \"Cryo-electron microscopy (cryo-EM) structural determination at ~4 Å resolution\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — atomic-resolution cryo-EM structure with direct structural comparison to TRPV1, identifying specific gating mechanism\",\n      \"pmids\": [\"26779611\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Full-length TRPV2 cryo-EM structure at ~5 Å shows two constrictions (upper and lower gates), with wider upper and lower gates compared to closed and agonist-activated TRPV1, suggesting structural diversity among TRPV channels contributes to functional divergence.\",\n      \"method\": \"Cryo-electron microscopy (cryo-EM) of full-length TRPV2\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — full-length cryo-EM structure with direct structural comparison providing mechanistic insight into gating\",\n      \"pmids\": [\"27021073\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CBD binds TRPV2 through a hydrophobic pocket between S5 and S6 helices of adjacent subunits, a site distinct from known ligand/lipid sites in other TRP channels; the S4-S5 linker plays a critical role in channel gating upon CBD binding. Two distinct TRPV2 apo states were visualized in a lipid environment.\",\n      \"method\": \"Cryo-EM of full-length rat TRPV2 in nanodiscs in apo and CBD-bound states\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structures of multiple states with identified binding site and gating mechanism\",\n      \"pmids\": [\"31566564\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Crystal structures of rabbit TRPV2 in Ca2+-bound and resiniferatoxin (RTx)+Ca2+-bound forms reveal that RTx binding leads to two-fold symmetric opening of the selectivity filter wide enough for large organic cation permeation, establishing a structural basis for dual Ca2+ and large organic cation permeation.\",\n      \"method\": \"X-ray crystallography at 3.9 Å (Ca2+-bound) and 3.1 Å (RTx+Ca2+-bound) with functional electrophysiological characterization\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structures combined with functional characterization, multiple orthogonal methods\",\n      \"pmids\": [\"29728656\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Cryo-EM structures of rat TRPV2 reveal fully open and partially open states and resolve the full-length pore turret; activity assays demonstrate the pore turret is important for channel function, and structural data suggest lipid binding at the vanilloid pocket can regulate the lower gate and couple to the upper gate through a pore-turret-facilitated mechanism.\",\n      \"method\": \"Cryo-EM at 4.0 Å and 3.6 Å resolution combined with channel activity assays\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structures at multiple resolutions combined with functional assays\",\n      \"pmids\": [\"30598551\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"RTx induces two-fold symmetric conformations of TRPV2 in both nanodisc and amphipol environments (more pronounced in nanodiscs), establishing that symmetry transitions during gating are an intrinsic property of TRPV2 and not solely due to crystal packing.\",\n      \"method\": \"Cryo-EM of full-length rabbit TRPV2 in complex with RTx in nanodiscs and amphipol\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM in two distinct environments with replicated finding of symmetry transition\",\n      \"pmids\": [\"31090543\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Cryo-EM structures of rat TRPV2 in lipid nanodiscs activated by 2-APB identify a TRPV2-specific binding site at the interface of S5 of one monomer and the S4-S5 linker of the adjacent monomer; His521 and Rac539 are key residues for 2-APB activation confirmed by mutagenesis and electrophysiology. Simultaneous binding of 2-APB and CBD was demonstrated structurally.\",\n      \"method\": \"Cryo-EM in lipid nanodiscs, in silico docking, electrophysiological studies, mutagenesis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure with mutagenesis validation and electrophysiology, multiple orthogonal methods\",\n      \"pmids\": [\"35484159\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Cryo-EM structures at 2.8–3.3 Å reveal an endogenous cholesterol molecule inside the vanilloid binding pocket (VBP) of TRPV2 with 'head down, tail up' configuration that antagonizes ligand activation; methyl-β-cyclodextrin removes cholesterol from VBP; estradiol potentiates 2-APB activation by disturbing cholesterol binding; 2-APB binds within the VBP.\",\n      \"method\": \"Cryo-EM at 2.8–3.3 Å resolution; pharmacological assays\",\n      \"journal\": \"Nature chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution cryo-EM structures of multiple states with functional validation\",\n      \"pmids\": [\"36163384\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CBD sensitizes TRPV2 current responses to 2-APB by over two orders of magnitude without sensitizing to heat; cryo-EM reveals a new small-molecule binding site in the pore domain in addition to the previously reported CBD site. Strong sensitization by CBD is specific to TRPV2 (and TRPV3) and not transferred to TRPV1 by mutations at the CBD binding site or pore domain.\",\n      \"method\": \"Patch-clamp electrophysiology, cryo-EM, mutagenesis\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure combined with electrophysiology and mutagenesis, multiple orthogonal methods\",\n      \"pmids\": [\"37199723\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"TRPV2 Ca2+-dependent desensitization is mediated by hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2), not calmodulin; simultaneous confocal imaging and electrophysiology showed TRPV2 desensitization was concomitant with PIP2 depletion. Calmodulin inhibitors and mutant calmodulin did not alter desensitization.\",\n      \"method\": \"Whole-cell patch-clamp, simultaneous confocal imaging with fluorescent PIP2-binding probe, calmodulin inhibitors, mutant calmodulin co-expression\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — multiple orthogonal methods (electrophysiology, live imaging, pharmacology, molecular tools) in single study\",\n      \"pmids\": [\"20926660\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Oxidation of methionine residues M528 and M607 activates and sensitizes TRPV2 to heat; chloramine-T, UVA light, and ROS-producing photosensitizers activate TRPV2 in excised inside-out patches (direct channel effect); DTT plus methionine sulfoxide reductase partially reverses activation; mass spectrometry confirms oxidation of these residues; macrophage phagocytosis is reduced by TRPV2 inhibitor or DTT.\",\n      \"method\": \"Electrophysiology (whole-cell and excised inside-out patches), site-directed mutagenesis (M528I, M607I), mass spectrometry on purified TRPV2 protein, pharmacological assays in macrophages\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with mutagenesis and MS validation, multiple orthogonal methods\",\n      \"pmids\": [\"31719194\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"JAK1 mediates TRPV2 tyrosine phosphorylation at Tyr335, Tyr471, and Tyr525; enhanced tyrosine phosphorylation alters chemical and thermal sensitivity of TRPV2 in macrophages and DRG neurons; PTPN1 dephosphorylates TRPV2, dynamically balancing its activity; JAK1 phosphorylation is required for TRPV2 activity and macrophage phagocytic ability.\",\n      \"method\": \"Electrophysiology, site-directed mutagenesis, kinase/phosphatase assays, phagocytosis assays in macrophages and DRG neurons\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — identification of specific phosphorylation sites with writer (JAK1) and eraser (PTPN1) plus functional validation\",\n      \"pmids\": [\"35686730\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Calmodulin binds to the C-terminus of TRPV2 (residues 654–683) via a 1-5-10 consensus motif; R679A and K681A mutations reduce binding affinity by 50%, and double mutation K661A/K664A reduces affinity by 75%, identifying basic residues critical for calmodulin interaction.\",\n      \"method\": \"In vitro calmodulin binding assays with peptides, site-directed mutagenesis\",\n      \"journal\": \"Amino acids\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro peptide binding with mutagenesis, single lab, peptide-based (not full channel)\",\n      \"pmids\": [\"20686800\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"TRPV1 and TRPV2 form heteromeric complexes, as demonstrated by co-immunoprecipitation from HEK cells, F-11 cells, and rat DRG lysates; a small population of native DRG neurons co-expresses both channels at the cell surface.\",\n      \"method\": \"Co-immunoprecipitation from transfected mammalian cells and native rat DRG; immunofluorescence co-localization\",\n      \"journal\": \"Neuroreport\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — reciprocal co-IP in both heterologous and native cells, confirmed by immunofluorescence\",\n      \"pmids\": [\"16237318\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"TRPV2 forms a complex with PKA and the A-kinase adapter protein ACBD3 in mast cells; TRPV2 is surface-localized and functionally coupled to Ca2+ fluxes and degranulation; cAMP/PKA-dependent regulated phosphorylation is proposed as a modulation mechanism for TRPV2.\",\n      \"method\": \"Co-immunoprecipitation, calcium flux assays, degranulation assays, surface localization by immunostaining in mast cells\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP identifying PKA-ACBD3-TRPV2 complex with functional Ca2+ and degranulation readouts, single lab\",\n      \"pmids\": [\"15249591\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"RGA protein forms a physiological complex with TRPV2 in mast cells; overexpression of RGA potentiates basal surface localization of TRPV2; elevations in cytosolic cAMP drive plasma membrane localization of TRPV2 in mast cells.\",\n      \"method\": \"Co-immunoprecipitation with polyclonal anti-RGA antibody, flow cytometry for surface TRPV2 quantification, overexpression studies\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP confirming physiological complex, surface expression quantification, single lab\",\n      \"pmids\": [\"15547947\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"In pancreatic beta-cells, insulin induces translocation of TRPV2 from cytoplasm to the plasma membrane via the insulin receptor/PI3K pathway; this translocation increases Ca2+ entry and is required for autocrine insulin secretion stimulated by glucose; knockdown of TRPV2 or insulin receptor attenuates these effects.\",\n      \"method\": \"GFP-TRPV2 live-cell imaging, Myc-tagged TRPV2 surface detection, fura-2 Ca2+ imaging, shRNA knockdown, insulin receptor knockout beta-cells\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (live imaging, Ca2+ imaging, shRNA KD, receptor KO), replicated in primary beta-cells and cell lines\",\n      \"pmids\": [\"18984736\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Insulin/PI3K signaling accelerates glucose-induced first-phase insulin secretion by recruiting TRPV2 to the plasma membrane in beta-cells; PI3K inhibition abolishes insulin-induced rapid exocytotic response; TRPV2 inhibition (tranilast) or shRNA suppresses first-phase but not second-phase insulin secretion.\",\n      \"method\": \"Total internal reflection fluorescent microscopy (TIRFM) for exocytosis, Ca2+ imaging, PI3K inhibition, tranilast pharmacology, shRNA knockdown\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — TIRFM exocytosis imaging combined with pharmacology and shRNA, multiple orthogonal methods\",\n      \"pmids\": [\"20854263\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"PI3K promotes TRPV2 channel activity independently of channel translocation to the plasma membrane; cytotoxicity (a read-out of channel activity) is prevented by a pore-domain charge substitution or reduced extracellular Ca2+; PI3K inhibition decreases TRPV2 activity without affecting plasma membrane trafficking.\",\n      \"method\": \"Cytotoxicity assays, stable transfection electrophysiology, direct measurement of cell surface TRPV2 expression, pore-domain mutagenesis\",\n      \"journal\": \"Cell calcium\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cytotoxicity and surface expression assays with mutagenesis, challenges prior trafficking model\",\n      \"pmids\": [\"16533525\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Lysophospholipids (LPC and LPI) activate TRPV2 via Gq/Go-protein and PI3,4-kinase signaling, causing TRPV2 translocation to the plasma membrane, Ca2+ influx, and increased prostate cancer cell migration; activation depends on lysophospholipid side-chain length and head-group nature.\",\n      \"method\": \"Ca2+ imaging, TRPV2 translocation assays, migration assays, pharmacological signaling pathway dissection in PC3 cells\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — multiple assays (Ca2+ imaging, translocation, migration) with pharmacological pathway dissection, single lab\",\n      \"pmids\": [\"19321128\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Adrenomedullin induces prostate and urothelial cancer cell migration and invasion through TRPV2 translocation to the plasma membrane and subsequent increase in resting calcium levels.\",\n      \"method\": \"TRPV2 translocation assays, Ca2+ imaging, migration and invasion assays in cancer cell lines\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — translocation and Ca2+ imaging with migration assays, single lab\",\n      \"pmids\": [\"23741410\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Focal mechanical stress applied to HT1080 cells causes TRPV2 translocation to the site of stress in a PI3K/Rac1-dependent manner and increases sub-plasma membrane Ca2+ concentration; this Ca2+ elevation requires extracellular Ca2+ and TRPV2, as demonstrated by ruthenium red inhibition and TRPV2 knockdown.\",\n      \"method\": \"Live GFP-TRPV2 and RFP-Akt imaging, mechanical stress application by glass pipette, ruthenium red pharmacology, TRPV2 siRNA knockdown, dominant-negative Rac\",\n      \"journal\": \"Physiological reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live imaging with siRNA and pharmacological validation, PI3K/Rac pathway dissection\",\n      \"pmids\": [\"25677550\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TRPV2 is critical for maintenance of cardiac structure and function; conditional cardiac-specific elimination of TRPV2 causes disorganization of intercalated discs, myocardial conduction defects, impaired Ca2+ handling, and reduced IGF-1 secretion in response to stretch; IGF-1 receptor/PI3K/Akt signaling is significantly downregulated in TRPV2-deficient hearts; IGF-1 administration partially rescues cardiomyopathy.\",\n      \"method\": \"Conditional TRPV2 knockout in adult mice, echocardiography, single cardiomyocyte Ca2+ handling, neonatal cardiomyocyte stretch experiments, Western blotting, IGF-1 rescue experiments\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with multiple functional readouts and pathway rescue, replicated across developmental stages\",\n      \"pmids\": [\"24874017\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Sarcolemmal accumulation of TRPV2 is elevated in dilated cardiomyopathy (DCM) patients and three animal models; overexpression of TRPV2 N-terminal domain blocks plasma membrane accumulation and Ca2+ influx, reduces CaMKII phosphorylation and ROS production, prevents ventricular dilation and fibrosis, and improves survival; TRPV2 inhibitor tranilast suppresses DCM progression.\",\n      \"method\": \"Immunological analyses, transgenic/adenoviral N-terminal domain overexpression in DCM animals, Western blotting, echocardiography, survival analysis, tranilast pharmacology\",\n      \"journal\": \"Cardiovascular research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — gain-of-function and loss-of-function in multiple animal models with mechanistic downstream pathway characterization\",\n      \"pmids\": [\"23786999\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"In dystrophic (mdx) cardiomyocytes, TRPV2 is overexpressed and translocated from intracellular compartments to the sarcolemma and T-tubules; pharmacological inhibition, pore-blocking antibodies, and siRNA ablation of TRPV2 protect mdx cells from stretch-induced abnormal Ca2+ signals, establishing TRPV2 as a stretch-activated Ca2+ influx channel in dystrophic cardiomyopathy.\",\n      \"method\": \"Western blotting, immunocytochemistry, biotinylation assays, patch-clamp pharmacology, confocal Ca2+ imaging, pore-blocking antibodies, siRNA knockdown\",\n      \"journal\": \"Cardiovascular research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (biochemical, imaging, antibody blocking, siRNA) establishing TRPV2 in stretch-activated Ca2+ pathway\",\n      \"pmids\": [\"25616416\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"TRPV2 knockout mice have reduced thermogenic gene expression in brown adipose tissue in response to β-adrenergic receptor stimulation, increased body weight and fat, and cold intolerance, indicating TRPV2 plays a role in BAT thermogenesis; Ca2+ influx via TRPV2 is required for thermogenic gene induction.\",\n      \"method\": \"TRPV2 KO mice, gene expression analysis, β-adrenergic stimulation experiments, intracellular Ca2+ manipulation\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse with Ca2+ manipulation and gene expression readouts, single lab\",\n      \"pmids\": [\"26882545\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"TRPV2 activation inhibits spontaneous intestinal circular muscle contraction through nitric oxide (NO) production; mechanical stimuli activate TRPV2-like inward currents in myenteric neurons (inhibited by tranilast); TRPV2 agonists increase intestinal NO production and accelerate gastrointestinal transit in vivo.\",\n      \"method\": \"Dissociated myenteric neuron patch-clamp, isolated intestine contraction assays, NO synthase pathway inhibitors, Ca2+ imaging, in vivo gastrointestinal transit assay\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — patch-clamp, pharmacology, ex vivo and in vivo assays establishing TRPV2→NO→motility pathway\",\n      \"pmids\": [\"21147993\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"TRPV2 contributes to stretch-activated cation currents and myogenic constriction in retinal arterioles; hypoosmotic stretch-induced Ca2+ influx in retinal VSMCs is blocked by tranilast and TRPV2 pore-blocking antibodies; preincubation with TRPV2 blocking antibodies prevents development of myogenic tone.\",\n      \"method\": \"Patch-clamp electrophysiology, Fura-2 Ca2+ microfluorimetry, pressure myography, TRPV2 pore-blocking antibodies, tranilast pharmacology\",\n      \"journal\": \"Investigative ophthalmology & visual science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple electrophysiological and pharmacological methods with specific pore-blocking antibodies\",\n      \"pmids\": [\"27784066\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"RANKL upregulates TRPV2 expression in preosteoclasts and drives spontaneous Ca2+ oscillations and transient inward cation currents; TRPV2 silencing reduces Ca2+ oscillation frequency and current amplitude, decreases NFATc1 expression and nuclear translocation, and inhibits osteoclastogenesis.\",\n      \"method\": \"DNA microarray, siRNA silencing of TRPV2, Ca2+ imaging, patch-clamp, Western blotting for NFATc1\",\n      \"journal\": \"Cell calcium\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA with Ca2+ imaging and electrophysiology identifying RANKL→TRPV2→NFATc1 pathway, single lab\",\n      \"pmids\": [\"20980052\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TRPV2 in Ca2+-calcineurin-NFAT signaling regulates RANKL-dependent osteoclastic differentiation in multiple myeloma; TRPV2 gates Ca2+ influx in MM cells in high Ca2+ environment; SKF96365 inhibition of TRPV2 attenuates osteoclast formation in vitro.\",\n      \"method\": \"Fluo-4 Ca2+ staining, Western blotting, ChIP assays, ELISA, TRAP staining, TRPV2 inhibitor\",\n      \"journal\": \"Cell communication and signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — multiple biochemical assays with pharmacological inhibition establishing pathway\",\n      \"pmids\": [\"30326911\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Replication stress causes ssDNA/dsDNA to translocate to the cytoplasm, activating cGAS and producing cGAMP; cGAMP binding to STING causes its dissociation from TRPV2, derepressing TRPV2 and causing Ca2+ release from the ER, which activates CaMKK2/AMPK to protect replication forks from Exo1-mediated degradation.\",\n      \"method\": \"Genetic manipulation, biochemical co-immunoprecipitation (STING-TRPV2 interaction), Ca2+ measurements, epistasis analysis\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP of STING-TRPV2 interaction with functional pathway epistasis, single lab\",\n      \"pmids\": [\"36696898\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TRPV2 in myeloid cells facilitates virus penetration by promoting cell membrane tension and mobility through the Ca2+-LRMDA axis; Ca2+-impermeable TRPV2-E572Q mutant fails to restore viral infection in TRPV2 KO cells; TRPV2 KO leads to downregulation of Lrmda and reduced membrane tension; LRMDA complementation restores membrane tension and viral penetration.\",\n      \"method\": \"TRPV2 conditional KO, reconstitution with TRPV2 or Ca2+-impermeable mutant, LRMDA knockdown/complementation, membrane tension and mobility assays\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic reconstitution with Ca2+-impermeable mutant and downstream LRMDA axis characterization\",\n      \"pmids\": [\"36261399\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Phagocytosis in primary human macrophages requires TRPV2-mediated Ca2+ influx; P. aeruginosa recruits TRPV2 to the cell surface; TRPV2 must be localized in lipid rafts to be functional for phagocytosis; CF macrophages display deficient TRPV2 function and impaired phagocytosis.\",\n      \"method\": \"Pharmacological inhibition of TRPV2, siRNA knockdown, phagocytosis assays, Ca2+ imaging, lipid raft fractionation\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple methods including lipid raft fractionation and siRNA in primary human macrophages\",\n      \"pmids\": [\"29523858\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TRPV2 is highly expressed in B cells and required for B cell immunological synapse formation and activation; the pore and N-terminal domains are critical for cation permeation and mechanosensation; TRPV2 deficiency in B cells impairs antibody responses; TRPV2 activity promotes membrane potential depolarization and cytoskeleton remodeling during antigen stimulation.\",\n      \"method\": \"B cell-specific TRPV2 KO mice, immunological synapse imaging, antibody response assays, domain-specific mutagenesis\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — B cell-specific KO with mechanistic domain analysis and functional immune readouts, single lab\",\n      \"pmids\": [\"38353705\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TRPV2 silencing increases glioma (U87MG) cell proliferation, rescues cells from Fas-induced apoptosis, downregulates Fas and procaspase-8 expression, and upregulates Bcl-XL; these effects depend on ERK activation; ERK inhibition (PD98059) restores Akt/PKB activation, reduces Bcl-XL, promotes Fas expression, and increases apoptosis sensitivity in TRPV2-silenced cells.\",\n      \"method\": \"siRNA silencing, RT-Profiler PCR array, BrdU proliferation assay, flow cytometry apoptosis, ERK inhibitor PD98059\",\n      \"journal\": \"Carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — siRNA with multiple downstream molecular readouts and pharmacological pathway validation\",\n      \"pmids\": [\"20093382\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TRPV2 localizes at the leading edge in dynamic nascent adhesions of invasive melanoma cells; TRPV2 activity regulates calcium-mediated activation of calpain and cleavage of talin, along with F-actin organization; TRPV2 silencing prevents aggressive migratory and invasive behavior; TRPV2 activity is sufficient to confer migratory and invasive potential.\",\n      \"method\": \"In vitro migration/invasion assays, in vivo mouse models, TRPV2 silencing, live-cell imaging of TRPV2 localization, calpain activity assays, talin cleavage Western blot, F-actin staining\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo assays with mechanistic calpain/talin pathway characterization and TRPV2 localization, single lab\",\n      \"pmids\": [\"36744297\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TRPV2 stimulation in rheumatoid arthritis fibroblast-like synoviocytes reduces FLS adhesion, decreases integrin (αν, β1, β3) localization to plasma membrane, reduces activated RhoA and Rac1 levels, decreases cofilin activation, and inhibits invasion; RhoA activators overcome TRPV2-induced suppression.\",\n      \"method\": \"TRPV2 pharmacological stimulation, FLS adhesion and invasion assays, integrin surface localization, RhoA/Rac1 activity assays, cofilin western blotting\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — pharmacological TRPV2 stimulation with multiple downstream signaling readouts, single lab\",\n      \"pmids\": [\"30851707\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"LL-37 activates TRPV2 and recruits it to pseudopodia via PI3K/AKT pathway activation, causing Ca2+ entry that cooperates with BKCa channel K+ efflux to drive cancer cell migration; LL-37 D-enantiomer has identical effects, suggesting membrane physical property modification rather than specific receptor binding is the mechanism.\",\n      \"method\": \"Ca2+ imaging, migration assays (wound healing), PI3K/AKT inhibition, D-enantiomer controls, confocal microscopy of TRPV2 localization\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Ca2+ imaging and migration assays with D-enantiomer mechanistic control and PI3K/AKT pathway validation\",\n      \"pmids\": [\"26993604\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Heat sensitivity of TRPV2 exhibits strong use dependence: prior heat activation decreases activation temperature threshold, reduces slope sensitivity, and accelerates activation time courses. Prior heat sensitizes agonist responses, but agonist activation does not sensitize heat responses (non-reciprocal cross-use-dependence), indicating separate temperature sensing and agonist activation pathways.\",\n      \"method\": \"Electrophysiology (patch-clamp), quantitative thermal activation analysis\",\n      \"journal\": \"Biophysical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — rigorous quantitative electrophysiology establishing use-dependence mechanism, single lab\",\n      \"pmids\": [\"27074678\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TRPV2 channels mediate osmotic cell swelling-induced insulin secretion in mouse beta-cells; TRPV2 siRNA knockdown and tranilast reduce hypotonic stimulation-induced Ca2+ elevation and insulin secretion; glucose-stimulated insulin secretion is also reduced by TRPV2 knockdown.\",\n      \"method\": \"Ca2+ imaging, siRNA knockdown, tranilast pharmacology, insulin secretion ELISA from isolated islets\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with Ca2+ imaging and functional insulin secretion assays\",\n      \"pmids\": [\"30649920\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TRPV2 dominant-negative expressing skeletal muscle fibres show slower membrane depolarization, diminished Ca2+ response, smaller regulatory volume increase (RVI), and decreased SPAK phosphorylation in response to hyperosmotic shock, suggesting TRPV2 activation depolarizes T-tubules, triggering Ca2+ release from sarcoplasmic reticulum and activating SPAK/NKCC1 for RVI.\",\n      \"method\": \"TRPV2 dominant-negative overexpression in skeletal muscle fibres, Ca2+ imaging, membrane potential measurements, SPAK phosphorylation Western blot, BAPTA chelation\",\n      \"journal\": \"The Journal of physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — dominant-negative model with multiple functional readouts and Ca2+ chelator controls\",\n      \"pmids\": [\"26108786\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"In the retinal pigment epithelium, TRPV2 mediates the sustained Ca2+ elevation phase of angiotensin II signaling; TRPV2 siRNA reduces the sustained phase of AngII-mediated Ca2+ transients by 53%; TRPV2 co-localizes with AT1R/Atrap complex; IGF-1 and CBD increase TRPV2 surface expression via PI3K.\",\n      \"method\": \"siRNA knockdown, Ca2+ imaging, SKF96365 pharmacology, immunostaining, co-localization analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — siRNA with pharmacology and Ca2+ imaging in primary porcine RPE cells\",\n      \"pmids\": [\"23185387\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"In the retinal pigment epithelium, IGF-1 increases TRPV2 surface expression and channel activity via PI3K; CBD increases TRPV2 surface expression (more than IGF-1) and channel activity; PI3K inhibitor LY294002 abolishes both effects; heat further potentiates CBD- but not IGF-1-stimulated conductance.\",\n      \"method\": \"Whole-cell patch-clamp, confocal microscopy for surface TRPV2 quantification, PI3K inhibition, IGF-1 and CBD pharmacology in ARPE-19 cells\",\n      \"journal\": \"Graefe's archive for clinical and experimental ophthalmology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — patch-clamp with surface expression quantification and pharmacological dissection of PI3K pathway\",\n      \"pmids\": [\"25616727\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"VRL-1 (TRPV2) expressed in F-11 cells is N-glycosylated when overexpressed heterologously, similar to VR1; endogenous VRL-1 in F-11 cells shows mainly cytoplasmic localization by immunofluorescence, whereas overexpressed rat VRL-1 appears mainly at the plasma membrane.\",\n      \"method\": \"RT-PCR, deglycosylation assay (N-linked glycosylation), immunofluorescence localization\",\n      \"journal\": \"European journal of biochemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, biochemical characterization only, indirect localization readout\",\n      \"pmids\": [\"14622291\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"TRPV2 activation inhibits differentiation of brown adipocytes in a dose-dependent manner during early differentiation stages via a calcineurin pathway; mechanical force also inhibits differentiation through TRPV2; these effects are significantly reduced in TRPV2 KO cells and reversed by calcineurin inhibitors (cyclosporine A, FK506).\",\n      \"method\": \"TRPV2 KO mouse adipocytes, TRPV2 agonist/antagonist pharmacology, mechanical stimulation, calcineurin inhibitors, differentiation markers\",\n      \"journal\": \"Pflugers Archiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO cells with pharmacological and mechanical stimulation establishing calcineurin pathway, single lab\",\n      \"pmids\": [\"27318696\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TRPV2 is a Ca2+-permeable, non-selective cation channel that adopts a homotetrameric structure with two gates (upper/selectivity filter and lower/S6), is tonically retained in intracellular pools (ER) under basal conditions, and is activated by diverse stimuli including noxious heat (>52°C), mechanical/osmotic stress, lipids (lysophospholipids, cholesterol acts as an endogenous inhibitor in the vanilloid binding pocket), and small-molecule agonists (cannabidiol, 2-APB, probenecid, resiniferatoxin) that bind distinct sites in or near the S5/S6 transmembrane domain; channel gating involves ankyrin-repeat domain rotation coupled to the TRP domain and S6, symmetry transitions at the selectivity filter, and modulation by PIP2 hydrolysis (mediating Ca2+-dependent desensitization) and post-translational modifications including JAK1-mediated tyrosine phosphorylation (Tyr335/471/525, activating) and methionine oxidation (M528/M607, activating); plasma membrane translocation—triggered by PI3K, insulin, growth factors, cAMP/PKA, or mechanical stimuli—is a key regulatory mechanism controlling TRPV2 activity in non-neuronal cells, and TRPV2 engages downstream signaling cascades including Ca2+-calcineurin-NFAT (osteoclastogenesis), CaMKII, PI3K/Akt (cardiac function, cancer migration), RhoA/Rac1 (invasion), calpain/talin (leading edge dynamics), NO production (intestinal motility), and the cGAS/STING/TRPV2/CaMKK2/AMPK axis (replication fork protection), with established roles in cardiac mechanosensation, mast cell degranulation, macrophage phagocytosis, B cell activation, beta-cell insulin secretion, brown adipose thermogenesis, and cancer cell migration/invasion.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TRPV2 is a Ca2+-permeable, non-selective cation channel that functions as a polymodal sensor of heat, mechanical/osmotic stress, lipids, and small-molecule agonists, transducing these stimuli into Ca2+ signals that drive cytoskeletal remodeling, secretion, and gene expression across diverse non-neuronal cell types [#3, #16, #35]. Structurally it is a homotetramer with an upper (selectivity filter) and lower (S6) gate, in which agonist (resiniferatoxin) binding drives a two-fold symmetric opening of the selectivity filter wide enough to permeate large organic cations, while rotation of the ankyrin-repeat domain couples through the TRP domain to S6 to open the pore [#0, #3, #5]. Distinct ligand sites govern gating: cannabidiol binds a hydrophobic pocket between S5 and S6 of adjacent subunits acting through the S4-S5 linker, 2-APB binds a TRPV2-specific S5/S4-S5 interface site (His521/Arg539), and an endogenous cholesterol molecule occupies the vanilloid binding pocket as an inhibitor that is relieved by methyl-\\u03b2-cyclodextrin or estradiol [#2, #6, #7]. Channel activity is tuned post-translationally by Ca2+-dependent desensitization via PIP2 hydrolysis [#9], methionine oxidation at M528/M607 (heat-sensitizing and required for macrophage phagocytosis) [#10], and JAK1-mediated tyrosine phosphorylation at Tyr335/471/525 balanced by the phosphatase PTPN1 [#11]. A central regulatory theme is stimulus-triggered translocation from intracellular pools to the plasma membrane, driven by insulin/PI3K, growth factors, lysophospholipids, adrenomedullin, mechanical stress, and cAMP, which controls Ca2+ entry in beta-cell insulin secretion, cancer cell migration, and cardiac mechanosensation [#16, #19, #21, #23]. Through this gating and trafficking, TRPV2 engages downstream Ca2+-calcineurin-NFAT signaling in osteoclastogenesis and brown adipocyte regulation [#28, #44], calpain/talin and RhoA/Rac1 cascades governing leading-edge dynamics and invasion [#35, #36], IGF-1/PI3K/Akt signaling sustaining cardiac structure and function [#22, #23], and a cytoplasmic cGAS/STING-derepressed Ca2+ release pathway that activates CaMKK2/AMPK to protect replication forks [#30].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Established the basic biochemical and localization properties of TRPV2, addressing whether the channel is processed and where it resides in cells.\",\n      \"evidence\": \"RT-PCR, N-glycosylation deglycosylation assays, and immunofluorescence in F-11 cells\",\n      \"pmids\": [\"14622291\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single lab, indirect localization readout\", \"Overexpression artifact possible for plasma membrane signal\", \"No functional channel measurement\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Showed that stimulus-driven plasma membrane translocation, not just intrinsic gating, controls TRPV2 function, answering how an intracellular channel becomes active for physiological Ca2+ entry.\",\n      \"evidence\": \"GFP-TRPV2 imaging, surface detection, Ca2+ imaging, shRNA knockdown, and insulin receptor knockout in beta-cells (also #17, #19, #20, #21)\",\n      \"pmids\": [\"18984736\", \"20854263\", \"19321128\", \"23741410\", \"25677550\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular machinery of vesicular trafficking not defined\", \"Translocation vs. direct activity contributions not always separated\", \"PI3K can promote activity independent of trafficking (#18), unresolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Resolved the mechanism of Ca2+-dependent desensitization, distinguishing PIP2 hydrolysis from calmodulin as the negative regulator of the channel.\",\n      \"evidence\": \"Whole-cell patch-clamp with simultaneous confocal PIP2 probe imaging and calmodulin perturbation\",\n      \"pmids\": [\"20926660\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Calmodulin still binds the C-terminus (#12) with unclear functional role\", \"Structural basis of PIP2 action not resolved\", \"Lipid binding site not mapped in this study\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Provided the first atomic-scale gating model by showing ankyrin-repeat domain rotation coupled through the TRP domain to S6, and defined two-gate architecture.\",\n      \"evidence\": \"Cryo-EM of rabbit and full-length TRPV2 (also #1)\",\n      \"pmids\": [\"26779611\", \"27021073\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Resolution limited (~4-5 \\u00c5)\", \"Ligand-bound and physiological lipid states not yet captured\", \"Coupling of upper and lower gates incompletely defined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined the structural basis for dual Ca2+ and large organic cation permeation by showing agonist-induced two-fold symmetric selectivity filter opening, an intrinsic gating property.\",\n      \"evidence\": \"X-ray crystallography and cryo-EM with electrophysiology in Ca2+/RTx-bound states (also #4, #5)\",\n      \"pmids\": [\"29728656\", \"30598551\", \"31090543\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological trigger of symmetry transition in vivo unclear\", \"Pore turret role beyond functional importance not mechanistically dissected\", \"Heat-induced conformations not captured\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Mapped distinct small-molecule and lipid binding sites (CBD between S5/S6; later 2-APB at an S5/S4-S5 interface) and an endogenous cholesterol inhibitor in the vanilloid pocket, explaining polypharmacology and endogenous tone.\",\n      \"evidence\": \"Cryo-EM in nanodiscs with mutagenesis and electrophysiology (also #6, #7, #8)\",\n      \"pmids\": [\"31566564\", \"35484159\", \"36163384\", \"37199723\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous heat-sensing site distinct from agonist sites (#38) not structurally resolved\", \"Physiological regulation of cholesterol occupancy unknown\", \"How CBD sensitization to 2-APB but not heat is encoded structurally not fully explained\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified covalent activating modifications, establishing TRPV2 as an oxidation- and phosphorylation-gated channel with defined writers, erasers, and residues.\",\n      \"evidence\": \"Excised-patch electrophysiology, mutagenesis, mass spectrometry, and kinase/phosphatase assays (also #11)\",\n      \"pmids\": [\"31719194\", \"35686730\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological sources of oxidation in vivo not fully defined\", \"Crosstalk between oxidation, phosphorylation, and lipid regulation unmapped\", \"Structural consequences of modifications not visualized\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Established TRPV2 as a cardiac mechanosensor required for structural integrity and Ca2+ handling, linking it to IGF-1/PI3K/Akt signaling and disease.\",\n      \"evidence\": \"Conditional cardiac KO with echocardiography, Ca2+ handling, stretch experiments, and IGF-1 rescue (also #23, #24)\",\n      \"pmids\": [\"24874017\", \"23786999\", \"25616416\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct stretch-sensing mechanism at molecular level not resolved\", \"Relationship between sarcolemmal accumulation and pathology vs. protection context-dependent\", \"No timeline evidence of a human Mendelian mutation\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Connected TRPV2-mediated Ca2+ entry to effector pathways driving cell migration, invasion, and cytoskeletal remodeling in cancer and immune contexts.\",\n      \"evidence\": \"Silencing/pharmacology with calpain/talin, RhoA/Rac1, and ERK readouts and in vivo invasion models (also #34, #36, #37)\",\n      \"pmids\": [\"36744297\", \"20093382\", \"30851707\", \"26993604\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Largely single-lab studies per cell type\", \"Direct vs. indirect coupling to calpain/RhoA not fully established\", \"Context-dependent pro- vs. anti-invasive effects unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrated TRPV2's role in innate and adaptive immune cell function, including phagocytosis, viral penetration, and B cell synapse formation, via Ca2+ and membrane mechanics.\",\n      \"evidence\": \"siRNA/conditional KO, lipid raft fractionation, reconstitution with Ca2+-impermeable mutants, and functional immune assays (also #31, #33)\",\n      \"pmids\": [\"29523858\", \"36261399\", \"38353705\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Recruitment mechanism to phagocytic cup/synapse not fully defined\", \"LRMDA axis mechanistic detail incomplete\", \"Single-lab findings per immune cell type\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Placed TRPV2 in a genome-stability pathway, showing STING dissociation derepresses TRPV2 to release ER Ca2+ and protect replication forks via CaMKK2/AMPK.\",\n      \"evidence\": \"STING-TRPV2 co-immunoprecipitation, Ca2+ measurements, and pathway epistasis\",\n      \"pmids\": [\"36696898\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single Co-IP for STING-TRPV2 interaction without structural validation\", \"ER-resident vs. plasma membrane pool contribution not separated\", \"Generality across cell types untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the structurally defined heat-sensing pathway, distinct agonist/lipid sites, and post-translational modifications integrate with stimulus-gated trafficking to set cell-type-specific TRPV2 output remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of a heat-activated state\", \"Trafficking machinery and recruitment signals undefined\", \"Integration of oxidation, phosphorylation, lipid, and PIP2 inputs not unified mechanistically\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005216\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [10, 38]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [24, 33]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [14, 16, 24, 32]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [30]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [16, 43]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [16, 22, 28, 30]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [32, 33, 31]},\n      {\"term_id\": \"R-HSA-397014\", \"supporting_discovery_ids\": [22, 24, 40]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"TRPV1\", \"STING1\", \"PRKACA\", \"ACBD3\", \"CALM1\", \"PTPN1\", \"JAK1\", \"LRMDA\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}