{"gene":"TRPV1","run_date":"2026-06-10T10:51:56","timeline":{"discoveries":[{"year":2021,"finding":"Cryo-EM structural snapshots of TRPV1 revealed mechanism of polymodal functionality: protons, vanilloid agonists, and peptide toxins induce conformational transitions of the selectivity filter that permit permeation by small and large organic cations, with allosteric coupling identified between sites proximal to the selectivity filter and the cytoplasmic gate.","method":"Cryo-electron microscopy (cryo-EM) with multiple ligand conditions","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structural determination with multiple ligand states and functional validation in a single rigorous study","pmids":["34496225"],"is_preprint":false},{"year":2022,"finding":"Cryo-EM ensemble analysis of TRPV1 with resiniferatoxin (RTx) bound revealed a sequential conformational trajectory: intracellular gate opening occurs first, followed by selectivity filter dilation, then pore loop rearrangement to reach the final open state, demonstrating a concerted stepwise allosteric mechanism.","method":"Cryo-EM thermal titration ensemble analysis; site-directed mutagenesis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structural snapshots capturing intermediate states with functional validation","pmids":["35610228"],"is_preprint":false},{"year":2017,"finding":"Capsaicin binds to a pocket formed by TRPV1 transmembrane segments in a 'tail-up, head-down' configuration, mediated by hydrogen bonds and van der Waals interactions; upon binding, capsaicin stabilizes the open state by 'pull-and-contact' with the S4-S5 linker.","method":"Mutagenesis, patch-clamp recording, crystallography, cryo-EM, computational docking, molecular dynamic simulation","journal":"Protein & cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal structural and functional methods, replicated across approaches","pmids":["28044278"],"is_preprint":false},{"year":2006,"finding":"PI3K p85β subunit physically interacts with the N-terminal region of TRPV1 (demonstrated by yeast 2-hybrid, co-immunoprecipitation from HEK293 cells and DRG neurons, and in vitro pulldown), and this physical coupling facilitates NGF-mediated trafficking of TRPV1 to the plasma membrane, increasing channel number at the surface; wortmannin abolished NGF-mediated sensitization.","method":"Yeast two-hybrid, co-immunoprecipitation, in vitro pulldown, TIRF microscopy, electrophysiology, PI3K inhibitor (wortmannin)","journal":"The Journal of general physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP from two cell types plus in vitro reconstitution plus functional imaging, multiple orthogonal methods in single study","pmids":["17074976"],"is_preprint":false},{"year":2008,"finding":"AKAP150 associates with TRPV1 in trigeminal ganglia neurons and scaffolds PKA to mediate PKA-dependent phosphorylation and sensitization of TRPV1; siRNA knockdown of AKAP150 reduced PKA phosphorylation of TRPV1 and attenuated PKA sensitization of TRPV1 activity; in vivo AKAP antagonist reduced prostaglandin E2-induced thermal hyperalgesia.","method":"Co-immunoprecipitation, siRNA knockdown, Ca2+ accumulation assay in CHO cells, in vivo pharmacology","journal":"Pain","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP plus siRNA functional knockdown plus in vivo validation, multiple orthogonal methods","pmids":["18381233"],"is_preprint":false},{"year":2014,"finding":"TRPV1 and TRPA1 form functional heteromeric channels: TRPV1::TRPA1 concatemers form tetrameric channels (confirmed by AFM) with two TRPV1::TRPA1 units arranged face-to-face; these heteromers respond to TRPV1 agonists (capsaicin, acidic pH, ethanol) but not TRPA1 agonists, have only two capsaicin binding sites, show reduced total current, and TRPA1 presence exerts functional inhibition on TRPV1.","method":"Subunit concatemers, atomic force microscopy, electrophysiology, antibody epitope mapping","journal":"Pflugers Archiv : European journal of physiology","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — concatemer reconstitution plus AFM structural analysis plus patch-clamp, multiple orthogonal methods in single study","pmids":["24643480"],"is_preprint":false},{"year":2019,"finding":"PKC-mediated phosphorylation of TRPV1 at S801 contributes to inflammation-mediated sensitization of TRPV1 to ligand (capsaicin) but not to heat in vivo; S801A knock-in mice generated by CRISPR/Cas9 showed impaired PKC-induced sensitization of capsaicin-mediated currents in sensory neurons, attenuated PMA-evoked nocifensive responses, and reduced ongoing inflammatory pain, while basal sensitivity was preserved.","method":"CRISPR/Cas9 knock-in mice (S801A), patch-clamp electrophysiology, in vivo behavioral assays","journal":"The Journal of neuroscience : the official journal of the Society for Neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knock-in with defined phosphorylation site mutation, electrophysiology plus in vivo behavioral phenotype, multiple orthogonal readouts","pmids":["31676602"],"is_preprint":false},{"year":2013,"finding":"2-Arachidonoylglycerol (2-AG) and 1-arachidonoylglycerol (1-AG), diacylglycerol metabolites generated by phospholipase C, directly activate TRPV1 on native vascular sensory nerve fibers and in heterologously expressed TRPV1 in whole cells and inside-out membrane patches; monoacylglycerol lipase inhibitors augmented TRPV1-mediated responses to these endogenous ligands, and vasodilator responses to 2-AG were minor in TRPV1 knockout mice.","method":"Inside-out patch-clamp, whole-cell recordings, TRPV1 knockout mice, pharmacological inhibition, mass spectrometry (deuterium-labeled substrate metabolism)","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — inside-out patch (direct activation), KO mice validation, metabolic tracing, multiple orthogonal methods","pmids":["24312564"],"is_preprint":false},{"year":2005,"finding":"Insulin and IGF-I enhance TRPV1-mediated membrane currents through both increased receptor sensitivity and translocation of TRPV1 from cytosol to plasma membrane; this process requires receptor tyrosine kinase activation leading to PI3K and PKC-mediated phosphorylation of TRPV1.","method":"Electrophysiology in heterologous expression systems and DRG neurons, subcellular fractionation/translocation assay, pharmacological inhibition of PI3K and PKC","journal":"Molecular pain","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — electrophysiology plus translocation assay, single lab, two orthogonal methods","pmids":["15857517"],"is_preprint":false},{"year":2017,"finding":"TRPV1 activation stimulates a MAPK signaling pathway that causes β-arrestin2 to translocate to the nucleus, thereby preventing β-arrestin2 recruitment to the μ-opioid receptor (MOR), blocking MOR internalization and desensitization, and thus prolonging opioid analgesia during inflammation; this mechanism was absent in TRPV1-deficient mice.","method":"Cell signaling assays (MAPK, β-arrestin2 nuclear translocation), TRPV1 knockout mice, in vivo CFA inflammatory pain model, pharmacological opioid receptor antagonism","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 2 / Strong — signaling pathway dissection plus genetic KO with defined behavioral phenotype, multiple orthogonal methods replicated in vitro and in vivo","pmids":["30940767"],"is_preprint":false},{"year":2017,"finding":"TRPV1 physically binds MOR1 and blocks opioid-dependent phosphorylation of MOR1 while leaving G protein signaling intact; Ca2+ influx through TRPV1 activates calcium/calmodulin-dependent translocation of GRK5 away from the plasma membrane, thereby blocking its ability to phosphorylate MOR1.","method":"Co-immunoprecipitation (TRPV1-MOR1 binding), GRK5 localization assay, Ca2+ influx measurement, phosphorylation assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus GRK5 translocation assay plus phosphorylation readout, single lab","pmids":["29203659"],"is_preprint":false},{"year":2017,"finding":"TRPV1 regulates stress responses through HDAC2: TRPV1-deficient mice show reduced glucocorticoid receptor (GR)-mediated HDAC2 expression and activity; hippocampal knockdown of TRPV1 phenocopied stress resilience, and this behavioral effect was blocked by HDAC2 overexpression, establishing HDAC2 as a molecular link between TRPV1 activity and stress responses.","method":"Trpv1 knockout mice, hippocampal siRNA knockdown, HDAC2 overexpression rescue, behavioral stress assays","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO plus shRNA plus rescue experiment, single lab","pmids":["28402861"],"is_preprint":false},{"year":2007,"finding":"TRPV1 expression induces filopodia and neurite-like structures; TRPV1 localizes to filopodial tips; the N-terminal intracellular domain of TRPV1 is sufficient for filopodial initiation, while the C-terminal cytoplasmic domain stabilizes microtubules within filopodia; TRPV1 expression also alters cellular distribution and enhances endogenous expression of myosin IIA and myosin IIIA.","method":"Live cell microscopy, domain deletion constructs, immunofluorescence in F11, HeLa, and HEK cells","journal":"Journal of neurochemistry","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — domain dissection with multiple cell lines, live imaging, single lab","pmids":["17714453"],"is_preprint":false},{"year":2010,"finding":"TRPV1 is present in synaptic structures (co-localizes with pre- and postsynaptic proteins in cortical neuron spines), is detected in synaptosomes and synaptic transport vesicles, and its activation rapidly modulates vesicle recycling/fusion as demonstrated by FM4-64 dye imaging.","method":"Immunofluorescence co-localization, biochemical synaptosome fractionation, FM4-64 vesicle recycling assay, live cell microscopy","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — fractionation plus functional vesicle assay plus imaging, single lab, multiple methods","pmids":["20483957"],"is_preprint":false},{"year":2013,"finding":"TRPV1 activation in human corneal fibroblasts (HCF) by capsaicin induces Ca2+ influx, activates MAPK p38 signaling, and leads to IL-6 release; these effects were abolished by TRPV1 siRNA silencing or p38 MAPK inhibitor SB203580, establishing a TRPV1→p38 MAPK→IL-6 pathway in corneal inflammation.","method":"siRNA gene silencing, Ca2+ imaging, whole-cell patch-clamp, MAPK phosphorylation assays, IL-6 ELISA","journal":"Experimental eye research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown plus signaling pathway dissection plus functional cytokine readout, single lab","pmids":["23232207"],"is_preprint":false},{"year":2013,"finding":"Retinoids (naturally occurring and synthetic) directly activate recombinant and native TRPV1 ion channel; in vivo retinoid-induced pain behaviors were eliminated or significantly reduced by genetic or pharmacological inhibition of TRPV1, identifying TRPV1 as an ionotropic receptor for retinoids.","method":"Electrophysiology with recombinant TRPV1, TRPV1 knockout mice, pharmacological inhibition, in vivo nociceptive behavioral assays","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — recombinant channel activation plus genetic KO plus pharmacological inhibition, multiple orthogonal methods","pmids":["23925292"],"is_preprint":false},{"year":2020,"finding":"Resolvins (RvD1, RvD2, RvE1) prevent histamine-induced TRPV1 sensitization in DRG neurons; RvD2 reversal of TRPV1 sensitization is blocked by the GPR18 antagonist O-1918 and by pertussis toxin, establishing a GPR18/Gi-dependent pathway through which RvD2 desensitizes TRPV1.","method":"Live Ca2+ imaging of DRG neurons, pharmacological antagonism (GPR18, pertussis toxin), in vivo visceral hypersensitivity models","journal":"Gut","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Ca2+ imaging plus pharmacological pathway dissection plus in vivo validation, single lab","pmids":["33023902"],"is_preprint":false},{"year":2020,"finding":"PKCε-dependent phosphorylation of TRPV1 at sites T704 and S502 mediates carotid body sensing of asthma-associated Th2 cytokines; site-directed mutagenesis of these residues impaired the response, and systemic PKCε blockade reduced asthmatic bronchoconstriction without affecting oxygen sensing.","method":"Site-directed mutagenesis of TRPV1 T704 and S502, patch-clamp, nerve recordings, in situ rat preparations, pharmacological PKCε inhibition, in vivo allergen challenge","journal":"The Journal of physiology","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — mutagenesis of specific phosphorylation sites plus electrophysiology plus in vivo functional validation","pmids":["33180962"],"is_preprint":false},{"year":2008,"finding":"PIP2 directly potentiates TRPV1 in excised inside-out patches; polylysine (a cationic phosphoinositide sequestering agent) inhibited TRPV1 rather than potentiating it, contradicting the proposed tonic inhibition model for PIP2 on TRPV1.","method":"Inside-out patch-clamp electrophysiology, direct PIP2 application, polylysine sequestration","journal":"The Journal of general physiology","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct reconstitution in inside-out patches with defined lipid application, rigorous controls; reported in same study as PI3K binding (PMID 17074976)","pmids":["17074976"],"is_preprint":false},{"year":2016,"finding":"TRPV1 activation by capsaicin in SUM149PT triple-negative breast cancer cells induced Ca2+ influx (blocked by capsazepine), caused growth inhibition, and induced apoptosis and necrosis, establishing a functional TRPV1-mediated Ca2+-dependent anti-tumor signaling pathway.","method":"Ca2+ imaging, pharmacological inhibition (capsazepine), cell viability and apoptosis assays","journal":"Breast cancer (Dove Medical Press)","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, pharmacological inhibition only, no molecular mechanism beyond Ca2+ influx established","pmids":["28008282"],"is_preprint":false},{"year":2018,"finding":"Troglitazone activates TRPV1 to cause deacetylation of PPARγ in 3T3-L1 cells; TRPV1 inhibition by capsazepine prevented Troglitazone-induced Ca2+ influx, and inhibition of TRPV1 or Sirtuin 1 prevented PPARγ deacetylation, establishing a TRPV1→Ca2+→Sirtuin1→PPARγ deacetylation pathway.","method":"Ca2+ imaging, pharmacological inhibition (capsazepine), TRPV1 overexpression, Western blot for PPARγ acetylation, Sirtuin 1 inhibition","journal":"Biochimica et biophysica acta. Molecular basis of disease","confidence":"Low","confidence_rationale":"Tier 3 / Weak — pharmacological inhibition plus overexpression, single lab, no direct phosphorylation/deacetylation site identified","pmids":["30496795"],"is_preprint":false},{"year":2019,"finding":"TRPV1 and TRPV4 form functional heteromeric channel complexes in retinal microvascular endothelial cells (RMECs), demonstrated by proximity ligation assay and electrophysiological recording; pharmacological inhibition of either channel suppressed in vitro tubulogenesis and reduced retinal neovascularization in the oxygen-induced retinopathy mouse model.","method":"Proximity ligation assay, patch-clamp electrophysiology, in vitro angiogenesis assays, oxygen-induced retinopathy mouse model","journal":"Investigative ophthalmology & visual science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — PLA plus electrophysiology for heteromer identification plus in vivo functional validation","pmids":["31369032"],"is_preprint":false},{"year":2016,"finding":"In TRPV1-expressing HEK cells co-expressing the histamine H1 receptor (a PLC-coupled receptor), histamine stimulated 2-arachidonoylglycerol (2-AG) formation via diacylglycerol lipase, and the resulting 2-AG activated TRPV1 currents; this effect was augmented by monoacylglycerol lipase inhibition (JZL184) and abolished by diacylglycerol lipase inhibition, placing 2-AG generation downstream of PLC as a direct TRPV1 activator.","method":"Whole-cell patch-clamp, pharmacological enzyme inhibitors, mass spectrometry for 2-AG quantification","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — electrophysiology plus metabolic tracing, single lab, two orthogonal methods","pmids":["24312564"],"is_preprint":false},{"year":2015,"finding":"Ca2+ flowing through TRPV1 activates PLCδ isoforms, resulting in PIP2 depletion that limits TRPV1 channel activity and contributes to capsaicin-induced desensitization; PIP2 acts as a positive cofactor for TRPV1 via direct interaction, and its depletion is a mechanism of desensitization.","method":"Excised patch electrophysiology, PIP2 application/depletion experiments, PLCδ pharmacology (reviewed with cited primary data)","journal":"Pflugers Archiv : European journal of physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — inside-out patch data plus PLC pathway manipulation, findings from multiple labs synthesized","pmids":["25754030"],"is_preprint":false}],"current_model":"TRPV1 is a homotetrameric (or heteromeric with TRPA1/TRPV4) non-selective cation channel that is directly activated by noxious heat (>43°C), protons, capsaicin (binding a transmembrane pocket in a 'tail-up, head-down' configuration that stabilizes the open state via S4-S5 linker contact), endogenous lipids (anandamide, 2-arachidonoylglycerol, monoacylglycerols), retinoids, and peptide toxins; its gating involves sequential conformational changes from intracellular gate opening through selectivity filter dilation; its activity is bidirectionally regulated by plasma membrane PIP2 (positive cofactor whose depletion by Ca2+-activated PLCδ underlies desensitization) and by phosphorylation at multiple sites (including S801 by PKC and S502/T704 by PKCε) scaffolded by AKAP150, which controls sensitization; NGF-mediated sensitization occurs through physical coupling of PI3K-p85β to the TRPV1 N-terminus and consequent PI3K-dependent trafficking of TRPV1 to the plasma membrane; TRPV1 also binds and modulates μ-opioid receptor signaling by triggering Ca2+/calmodulin-dependent GRK5 membrane dissociation (blocking MOR phosphorylation) and by promoting nuclear β-arrestin2 translocation to prevent MOR desensitization; in the CNS, TRPV1 is present at synapses, regulates vesicle recycling, and controls stress responses through a HDAC2-dependent pathway."},"narrative":{"mechanistic_narrative":"TRPV1 is a polymodal, non-selective cation channel that transduces noxious chemical and physical stimuli into nociceptive signaling and serves as a hub for inflammatory sensitization [PMID:34496225, PMID:31676602]. Cryo-EM studies establish that protons, vanilloid agonists, and peptide toxins drive selectivity-filter conformational transitions allosterically coupled to the cytoplasmic gate, and that channel opening proceeds as a sequential trajectory—intracellular gate opening, then selectivity filter dilation, then pore-loop rearrangement [PMID:34496225, PMID:35610228]. Capsaicin engages a transmembrane pocket in a 'tail-up, head-down' configuration and stabilizes the open state through 'pull-and-contact' with the S4-S5 linker [PMID:28044278]. Beyond exogenous vanilloids, TRPV1 is directly activated by endogenous lipids, including the diacylglycerol metabolites 2-AG and 1-AG generated downstream of phospholipase C, and by retinoids, defining it as an ionotropic receptor for these ligands [PMID:24312564, PMID:23925292]. Channel activity is tuned by membrane PIP2, which acts as a direct positive cofactor whose depletion by Ca2+-activated PLCδ underlies capsaicin desensitization [PMID:17074976, PMID:25754030], and by phosphorylation: AKAP150 scaffolds PKA to sensitize the channel [PMID:18381233], PKC phosphorylation at S801 mediates inflammatory sensitization to ligand [PMID:31676602], and PKCε phosphorylation at T704/S502 underlies cytokine sensing in the carotid body [PMID:33180962]. Growth-factor signaling sensitizes TRPV1 through PI3K p85β binding to its N-terminus and consequent trafficking to the plasma membrane [PMID:17074976, PMID:15857517]. TRPV1 also assembles into heteromeric channels with TRPA1 and TRPV4 that alter its gating and pharmacology [PMID:24643480, PMID:31369032]. Beyond its channel role, TRPV1 modulates μ-opioid receptor signaling by binding MOR1 and blocking GRK5- and β-arrestin2-dependent receptor phosphorylation and desensitization [PMID:30940767, PMID:29203659], and in the CNS it localizes to synapses, regulates vesicle recycling, and controls stress responses via a glucocorticoid receptor/HDAC2 pathway [PMID:20483957, PMID:28402861].","teleology":[{"year":2005,"claim":"Established that growth-factor receptor tyrosine kinase signaling sensitizes TRPV1 not only by raising sensitivity but by mobilizing the channel to the plasma membrane, introducing trafficking as a sensitization mechanism.","evidence":"Electrophysiology and subcellular fractionation in DRG neurons and heterologous cells with PI3K/PKC inhibitors (insulin/IGF-I)","pmids":["15857517"],"confidence":"Medium","gaps":["Direct kinase-channel contacts not mapped","Single-lab translocation assay"]},{"year":2006,"claim":"Defined a physical mechanism for NGF sensitization by showing PI3K p85β binds the TRPV1 N-terminus to drive surface trafficking, and clarified PIP2 as a direct positive cofactor in excised patches.","evidence":"Yeast two-hybrid, reciprocal Co-IP from HEK293 and DRG neurons, in vitro pulldown, TIRF, and inside-out patch-clamp with direct PIP2/polylysine application","pmids":["17074976"],"confidence":"High","gaps":["Structural basis of p85β-N-terminus binding unresolved","How trafficking couples to channel activation not detailed"]},{"year":2007,"claim":"Showed TRPV1 has cytoskeletal/morphogenic activity beyond ion conduction, with N- and C-terminal domains driving filopodia initiation and microtubule stabilization.","evidence":"Domain-deletion constructs and live imaging in F11, HeLa, and HEK cells","pmids":["17714453"],"confidence":"Medium","gaps":["Physiological relevance in neurons unclear","Mechanism linking channel to myosin upregulation unknown"]},{"year":2008,"claim":"Identified AKAP150 as the scaffold that targets PKA to TRPV1, providing a structural basis for kinase-dependent sensitization and inflammatory hyperalgesia.","evidence":"Co-IP from trigeminal neurons, siRNA knockdown, Ca2+ assay in CHO cells, and in vivo AKAP antagonism","pmids":["18381233"],"confidence":"High","gaps":["Phosphosites mediating PKA sensitization not defined here","AKAP150 binding interface on TRPV1 unmapped"]},{"year":2010,"claim":"Extended TRPV1 function to central synapses, showing presence in synaptic vesicles and rapid modulation of vesicle recycling.","evidence":"Synaptosome fractionation, immunocolocalization, and FM4-64 imaging in cortical neurons","pmids":["20483957"],"confidence":"Medium","gaps":["Endogenous synaptic ligand not identified","Single-lab, no genetic confirmation of synaptic role"]},{"year":2013,"claim":"Identified endogenous direct activators of TRPV1—PLC-derived monoacylglycerols and retinoids—broadening the channel's ligand repertoire and linking it to lipid signaling and retinoid-induced pain.","evidence":"Inside-out and whole-cell patch-clamp, TRPV1 knockout mice, MAGL inhibition, mass spectrometry; recombinant/native channel activation with retinoids and KO/pharmacology in nociception","pmids":["24312564","23925292"],"confidence":"High","gaps":["Binding site for monoacylglycerols/retinoids not structurally defined","Physiological concentrations driving activation in vivo uncertain"]},{"year":2013,"claim":"Demonstrated a downstream signaling output of TRPV1 in non-neuronal cells via a TRPV1→p38 MAPK→IL-6 inflammatory axis in corneal fibroblasts.","evidence":"siRNA silencing, Ca2+ imaging, patch-clamp, MAPK phospho-assays, IL-6 ELISA","pmids":["23232207"],"confidence":"Medium","gaps":["Whether this axis operates in vivo not tested","Single-lab cell-line study"]},{"year":2014,"claim":"Showed TRPV1 forms defined heteromeric channels with TRPA1, altering stoichiometry, agonist sensitivity, and current magnitude.","evidence":"Concatemers, atomic force microscopy, patch-clamp, epitope mapping","pmids":["24643480"],"confidence":"High","gaps":["Native abundance of TRPV1::TRPA1 heteromers in vivo unclear","Structural basis of functional inhibition by TRPA1 not resolved"]},{"year":2015,"claim":"Consolidated the PIP2/PLCδ feedback model of desensitization, with Ca2+ entry through TRPV1 activating PLCδ to deplete its own positive cofactor PIP2.","evidence":"Excised-patch electrophysiology and PLCδ pharmacology synthesized across labs","pmids":["25754030"],"confidence":"Medium","gaps":["Quantitative contribution of PIP2 depletion vs other desensitization routes unresolved"]},{"year":2016,"claim":"Showed that GPCR-evoked PLC signaling activates TRPV1 indirectly through DAG-lipase-generated 2-AG, linking H1 receptor signaling to channel gating.","evidence":"Whole-cell patch-clamp, DAGL/MAGL inhibitors, mass spectrometry in HEK cells co-expressing H1R","pmids":["24312564"],"confidence":"Medium","gaps":["Single-lab heterologous system","Native cell relevance not established here"]},{"year":2017,"claim":"Defined a non-canonical role for TRPV1 in prolonging opioid analgesia by binding MOR1 and blocking its phosphorylation/desensitization through Ca2+/calmodulin-dependent GRK5 displacement and MAPK-driven nuclear β-arrestin2 sequestration.","evidence":"Co-IP, GRK5 localization and phosphorylation assays, β-arrestin2 translocation, TRPV1 KO mice, CFA inflammatory pain model","pmids":["29203659","30940767"],"confidence":"Medium","gaps":["TRPV1-MOR1 binding interface not mapped","GRK5 mechanism from single lab without reciprocal structural validation"]},{"year":2017,"claim":"Linked TRPV1 to central stress regulation through a glucocorticoid receptor/HDAC2 transcriptional pathway, establishing a CNS behavioral output downstream of the channel.","evidence":"Trpv1 KO mice, hippocampal siRNA knockdown, HDAC2 overexpression rescue, behavioral stress assays","pmids":["28402861"],"confidence":"Medium","gaps":["How channel activity couples to GR/HDAC2 transcription unknown","Single-lab study"]},{"year":2019,"claim":"Genetically pinned PKC sensitization to a single residue, showing S801 phosphorylation selectively governs ligand (not heat) sensitization and inflammatory pain in vivo.","evidence":"CRISPR S801A knock-in mice, patch-clamp, nocifensive behavior","pmids":["31676602"],"confidence":"High","gaps":["Other PKC sites contributing to sensitization not addressed by this mutation"]},{"year":2019,"claim":"Demonstrated TRPV1::TRPV4 heteromers in vascular endothelium with a functional role in pathological angiogenesis.","evidence":"Proximity ligation assay, patch-clamp, angiogenesis assays, oxygen-induced retinopathy model","pmids":["31369032"],"confidence":"Medium","gaps":["Subunit stoichiometry of TRPV1::TRPV4 not resolved","Signaling downstream of heteromer in endothelium unclear"]},{"year":2020,"claim":"Identified PKCε phosphorylation of T704/S502 as the mechanism for carotid-body cytokine sensing, and a GPR18/Gi pathway by which resolvins desensitize TRPV1.","evidence":"Site-directed mutagenesis, patch-clamp, nerve recordings, in vivo allergen challenge; DRG Ca2+ imaging with GPR18 antagonist and pertussis toxin","pmids":["33180962","33023902"],"confidence":"Medium","gaps":["How distinct PKC isoforms select sites mechanistically unclear","Resolvin/GPR18 effector linking to channel not defined"]},{"year":2022,"claim":"Resolved the temporal order of TRPV1 gating, showing activation is a concerted stepwise allosteric process from gate to filter.","evidence":"Cryo-EM thermal-titration ensemble analysis with RTx plus mutagenesis","pmids":["35610228"],"confidence":"High","gaps":["How heat per se drives the same trajectory not directly captured","Lipid cofactor states during transitions not modeled"]},{"year":null,"claim":"How the channel's diverse signaling outputs (synaptic, MOR-modulatory, transcriptional/HDAC2, lipid-deacetylation) are mechanistically coupled to ion conduction versus protein-scaffolding functions remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking Ca2+ flux to nuclear/transcriptional outputs","Binding interfaces for most protein partners unmapped","Endogenous activating ligands for central roles unidentified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[0,1,2,5]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,15,7]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[7,18,22,23]},{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[0,15]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[3,8,18]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[13]}],"pathway":[{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[13]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,9,10,17]},{"term_id":"R-HSA-9709957","term_label":"Sensory Perception","supporting_discovery_ids":[0,2,15]}],"complexes":["TRPV1::TRPA1 heteromeric channel","TRPV1::TRPV4 heteromeric channel"],"partners":["PIK3R2 (P85Β)","AKAP150","TRPA1","TRPV4","OPRM1 (MOR1)","GRK5"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8NER1","full_name":"Transient receptor potential cation channel subfamily V member 1","aliases":["Capsaicin receptor","Osm-9-like TRP channel 1","OTRPC1","Vanilloid receptor 1"],"length_aa":839,"mass_kda":95.0,"function":"Non-selective calcium permeant cation channel involved in detection of noxious chemical and thermal stimuli (PubMed:11050376, PubMed:11243859, PubMed:11226139, PubMed:12077606). Seems to mediate proton influx and may be involved in intracellular acidosis in nociceptive neurons. Involved in mediation of inflammatory pain and hyperalgesia. Sensitized by a phosphatidylinositol second messenger system activated by receptor tyrosine kinases, which involves PKC isozymes and PCL. Activated by vanilloids, like capsaicin, and temperatures higher than 42 degrees Celsius (PubMed:37117175). Upon activation, exhibits a time- and Ca(2+)-dependent outward rectification, followed by a long-lasting refractory state. Mild extracellular acidic pH (6.5) potentiates channel activation by noxious heat and vanilloids, whereas acidic conditions (pH <6) directly activate the channel. Can be activated by endogenous compounds, including 12-hydroperoxytetraenoic acid and bradykinin. Acts as ionotropic endocannabinoid receptor with central neuromodulatory effects. 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ophthalmology & visual science","url":"https://pubmed.ncbi.nlm.nih.gov/31369032","citation_count":35,"is_preprint":false},{"pmid":"27227028","id":"PMC_27227028","title":"The involvement of TRPV1 in emesis and anti-emesis.","date":"2015","source":"Temperature (Austin, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/27227028","citation_count":34,"is_preprint":false},{"pmid":"29203659","id":"PMC_29203659","title":"TRPV1 is a physiological regulator of μ-opioid receptors.","date":"2017","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/29203659","citation_count":34,"is_preprint":false},{"pmid":"32274960","id":"PMC_32274960","title":"The role of TRPV1 channels in atherosclerosis.","date":"2020","source":"Channels (Austin, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/32274960","citation_count":33,"is_preprint":false},{"pmid":"18992356","id":"PMC_18992356","title":"Is TRPV1 a useful target in respiratory diseases?","date":"2008","source":"Pulmonary pharmacology & therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/18992356","citation_count":33,"is_preprint":false},{"pmid":"31620023","id":"PMC_31620023","title":"TRPV1 and TRPV1-Expressing Nociceptors Mediate Orofacial Pain Behaviors in a Mouse Model of Orthodontic Tooth Movement.","date":"2019","source":"Frontiers in physiology","url":"https://pubmed.ncbi.nlm.nih.gov/31620023","citation_count":33,"is_preprint":false},{"pmid":"36077412","id":"PMC_36077412","title":"TRPV1: A Common Denominator Mediating Antinociceptive and Antiemetic Effects of Cannabinoids.","date":"2022","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36077412","citation_count":32,"is_preprint":false},{"pmid":"39310069","id":"PMC_39310069","title":"TRPV1: The key bridge in neuroimmune interactions.","date":"2024","source":"Journal of intensive 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pharmacology & therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/21215321","citation_count":29,"is_preprint":false},{"pmid":"30496795","id":"PMC_30496795","title":"Troglitazone activates TRPV1 and causes deacetylation of PPARγ in 3T3-L1 cells.","date":"2018","source":"Biochimica et biophysica acta. Molecular basis of disease","url":"https://pubmed.ncbi.nlm.nih.gov/30496795","citation_count":29,"is_preprint":false},{"pmid":"35138618","id":"PMC_35138618","title":"TRPV1 in Pain and Itch.","date":"2021","source":"Advances in experimental medicine and biology","url":"https://pubmed.ncbi.nlm.nih.gov/35138618","citation_count":28,"is_preprint":false},{"pmid":"33255148","id":"PMC_33255148","title":"TRPV1 Channel: A Noxious Signal Transducer That Affects Mitochondrial Function.","date":"2020","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33255148","citation_count":28,"is_preprint":false},{"pmid":"30461371","id":"PMC_30461371","title":"Interaction between TRPV1-expressing neurons in the hypothalamus.","date":"2018","source":"Journal of neurophysiology","url":"https://pubmed.ncbi.nlm.nih.gov/30461371","citation_count":27,"is_preprint":false},{"pmid":"36589466","id":"PMC_36589466","title":"The interaction of TRPV1 and lipids: Insights into lipid metabolism.","date":"2022","source":"Frontiers in physiology","url":"https://pubmed.ncbi.nlm.nih.gov/36589466","citation_count":26,"is_preprint":false},{"pmid":"34421611","id":"PMC_34421611","title":"Metformin Attenuates Bone Cancer Pain by Reducing TRPV1 and ASIC3 Expression.","date":"2021","source":"Frontiers in pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/34421611","citation_count":26,"is_preprint":false},{"pmid":"28028935","id":"PMC_28028935","title":"Renoprotection: focus on TRPV1, TRPV4, TRPC6 and TRPM2.","date":"2016","source":"Acta physiologica (Oxford, England)","url":"https://pubmed.ncbi.nlm.nih.gov/28028935","citation_count":25,"is_preprint":false},{"pmid":"20932254","id":"PMC_20932254","title":"TRPV1 and synaptic transmission.","date":"2011","source":"Current pharmaceutical biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/20932254","citation_count":25,"is_preprint":false},{"pmid":"27483288","id":"PMC_27483288","title":"TRPV1 and TRPM8 in Treatment of Chronic Cough.","date":"2016","source":"Pharmaceuticals (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/27483288","citation_count":25,"is_preprint":false},{"pmid":"33180962","id":"PMC_33180962","title":"PKCε stimulation of TRPV1 orchestrates carotid body responses to asthmakines.","date":"2020","source":"The Journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/33180962","citation_count":25,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":47766,"output_tokens":6245,"usd":0.118486,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":15063,"output_tokens":5072,"usd":0.101057,"stage2_stop_reason":"end_turn"},"total_usd":0.219543,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2021,\n      \"finding\": \"Cryo-EM structural snapshots of TRPV1 revealed mechanism of polymodal functionality: protons, vanilloid agonists, and peptide toxins induce conformational transitions of the selectivity filter that permit permeation by small and large organic cations, with allosteric coupling identified between sites proximal to the selectivity filter and the cytoplasmic gate.\",\n      \"method\": \"Cryo-electron microscopy (cryo-EM) with multiple ligand conditions\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structural determination with multiple ligand states and functional validation in a single rigorous study\",\n      \"pmids\": [\"34496225\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Cryo-EM ensemble analysis of TRPV1 with resiniferatoxin (RTx) bound revealed a sequential conformational trajectory: intracellular gate opening occurs first, followed by selectivity filter dilation, then pore loop rearrangement to reach the final open state, demonstrating a concerted stepwise allosteric mechanism.\",\n      \"method\": \"Cryo-EM thermal titration ensemble analysis; site-directed mutagenesis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structural snapshots capturing intermediate states with functional validation\",\n      \"pmids\": [\"35610228\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Capsaicin binds to a pocket formed by TRPV1 transmembrane segments in a 'tail-up, head-down' configuration, mediated by hydrogen bonds and van der Waals interactions; upon binding, capsaicin stabilizes the open state by 'pull-and-contact' with the S4-S5 linker.\",\n      \"method\": \"Mutagenesis, patch-clamp recording, crystallography, cryo-EM, computational docking, molecular dynamic simulation\",\n      \"journal\": \"Protein & cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal structural and functional methods, replicated across approaches\",\n      \"pmids\": [\"28044278\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"PI3K p85β subunit physically interacts with the N-terminal region of TRPV1 (demonstrated by yeast 2-hybrid, co-immunoprecipitation from HEK293 cells and DRG neurons, and in vitro pulldown), and this physical coupling facilitates NGF-mediated trafficking of TRPV1 to the plasma membrane, increasing channel number at the surface; wortmannin abolished NGF-mediated sensitization.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, in vitro pulldown, TIRF microscopy, electrophysiology, PI3K inhibitor (wortmannin)\",\n      \"journal\": \"The Journal of general physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP from two cell types plus in vitro reconstitution plus functional imaging, multiple orthogonal methods in single study\",\n      \"pmids\": [\"17074976\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"AKAP150 associates with TRPV1 in trigeminal ganglia neurons and scaffolds PKA to mediate PKA-dependent phosphorylation and sensitization of TRPV1; siRNA knockdown of AKAP150 reduced PKA phosphorylation of TRPV1 and attenuated PKA sensitization of TRPV1 activity; in vivo AKAP antagonist reduced prostaglandin E2-induced thermal hyperalgesia.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, Ca2+ accumulation assay in CHO cells, in vivo pharmacology\",\n      \"journal\": \"Pain\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP plus siRNA functional knockdown plus in vivo validation, multiple orthogonal methods\",\n      \"pmids\": [\"18381233\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TRPV1 and TRPA1 form functional heteromeric channels: TRPV1::TRPA1 concatemers form tetrameric channels (confirmed by AFM) with two TRPV1::TRPA1 units arranged face-to-face; these heteromers respond to TRPV1 agonists (capsaicin, acidic pH, ethanol) but not TRPA1 agonists, have only two capsaicin binding sites, show reduced total current, and TRPA1 presence exerts functional inhibition on TRPV1.\",\n      \"method\": \"Subunit concatemers, atomic force microscopy, electrophysiology, antibody epitope mapping\",\n      \"journal\": \"Pflugers Archiv : European journal of physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — concatemer reconstitution plus AFM structural analysis plus patch-clamp, multiple orthogonal methods in single study\",\n      \"pmids\": [\"24643480\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PKC-mediated phosphorylation of TRPV1 at S801 contributes to inflammation-mediated sensitization of TRPV1 to ligand (capsaicin) but not to heat in vivo; S801A knock-in mice generated by CRISPR/Cas9 showed impaired PKC-induced sensitization of capsaicin-mediated currents in sensory neurons, attenuated PMA-evoked nocifensive responses, and reduced ongoing inflammatory pain, while basal sensitivity was preserved.\",\n      \"method\": \"CRISPR/Cas9 knock-in mice (S801A), patch-clamp electrophysiology, in vivo behavioral assays\",\n      \"journal\": \"The Journal of neuroscience : the official journal of the Society for Neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knock-in with defined phosphorylation site mutation, electrophysiology plus in vivo behavioral phenotype, multiple orthogonal readouts\",\n      \"pmids\": [\"31676602\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"2-Arachidonoylglycerol (2-AG) and 1-arachidonoylglycerol (1-AG), diacylglycerol metabolites generated by phospholipase C, directly activate TRPV1 on native vascular sensory nerve fibers and in heterologously expressed TRPV1 in whole cells and inside-out membrane patches; monoacylglycerol lipase inhibitors augmented TRPV1-mediated responses to these endogenous ligands, and vasodilator responses to 2-AG were minor in TRPV1 knockout mice.\",\n      \"method\": \"Inside-out patch-clamp, whole-cell recordings, TRPV1 knockout mice, pharmacological inhibition, mass spectrometry (deuterium-labeled substrate metabolism)\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — inside-out patch (direct activation), KO mice validation, metabolic tracing, multiple orthogonal methods\",\n      \"pmids\": [\"24312564\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Insulin and IGF-I enhance TRPV1-mediated membrane currents through both increased receptor sensitivity and translocation of TRPV1 from cytosol to plasma membrane; this process requires receptor tyrosine kinase activation leading to PI3K and PKC-mediated phosphorylation of TRPV1.\",\n      \"method\": \"Electrophysiology in heterologous expression systems and DRG neurons, subcellular fractionation/translocation assay, pharmacological inhibition of PI3K and PKC\",\n      \"journal\": \"Molecular pain\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — electrophysiology plus translocation assay, single lab, two orthogonal methods\",\n      \"pmids\": [\"15857517\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TRPV1 activation stimulates a MAPK signaling pathway that causes β-arrestin2 to translocate to the nucleus, thereby preventing β-arrestin2 recruitment to the μ-opioid receptor (MOR), blocking MOR internalization and desensitization, and thus prolonging opioid analgesia during inflammation; this mechanism was absent in TRPV1-deficient mice.\",\n      \"method\": \"Cell signaling assays (MAPK, β-arrestin2 nuclear translocation), TRPV1 knockout mice, in vivo CFA inflammatory pain model, pharmacological opioid receptor antagonism\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — signaling pathway dissection plus genetic KO with defined behavioral phenotype, multiple orthogonal methods replicated in vitro and in vivo\",\n      \"pmids\": [\"30940767\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TRPV1 physically binds MOR1 and blocks opioid-dependent phosphorylation of MOR1 while leaving G protein signaling intact; Ca2+ influx through TRPV1 activates calcium/calmodulin-dependent translocation of GRK5 away from the plasma membrane, thereby blocking its ability to phosphorylate MOR1.\",\n      \"method\": \"Co-immunoprecipitation (TRPV1-MOR1 binding), GRK5 localization assay, Ca2+ influx measurement, phosphorylation assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus GRK5 translocation assay plus phosphorylation readout, single lab\",\n      \"pmids\": [\"29203659\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TRPV1 regulates stress responses through HDAC2: TRPV1-deficient mice show reduced glucocorticoid receptor (GR)-mediated HDAC2 expression and activity; hippocampal knockdown of TRPV1 phenocopied stress resilience, and this behavioral effect was blocked by HDAC2 overexpression, establishing HDAC2 as a molecular link between TRPV1 activity and stress responses.\",\n      \"method\": \"Trpv1 knockout mice, hippocampal siRNA knockdown, HDAC2 overexpression rescue, behavioral stress assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO plus shRNA plus rescue experiment, single lab\",\n      \"pmids\": [\"28402861\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"TRPV1 expression induces filopodia and neurite-like structures; TRPV1 localizes to filopodial tips; the N-terminal intracellular domain of TRPV1 is sufficient for filopodial initiation, while the C-terminal cytoplasmic domain stabilizes microtubules within filopodia; TRPV1 expression also alters cellular distribution and enhances endogenous expression of myosin IIA and myosin IIIA.\",\n      \"method\": \"Live cell microscopy, domain deletion constructs, immunofluorescence in F11, HeLa, and HEK cells\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — domain dissection with multiple cell lines, live imaging, single lab\",\n      \"pmids\": [\"17714453\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"TRPV1 is present in synaptic structures (co-localizes with pre- and postsynaptic proteins in cortical neuron spines), is detected in synaptosomes and synaptic transport vesicles, and its activation rapidly modulates vesicle recycling/fusion as demonstrated by FM4-64 dye imaging.\",\n      \"method\": \"Immunofluorescence co-localization, biochemical synaptosome fractionation, FM4-64 vesicle recycling assay, live cell microscopy\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — fractionation plus functional vesicle assay plus imaging, single lab, multiple methods\",\n      \"pmids\": [\"20483957\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"TRPV1 activation in human corneal fibroblasts (HCF) by capsaicin induces Ca2+ influx, activates MAPK p38 signaling, and leads to IL-6 release; these effects were abolished by TRPV1 siRNA silencing or p38 MAPK inhibitor SB203580, establishing a TRPV1→p38 MAPK→IL-6 pathway in corneal inflammation.\",\n      \"method\": \"siRNA gene silencing, Ca2+ imaging, whole-cell patch-clamp, MAPK phosphorylation assays, IL-6 ELISA\",\n      \"journal\": \"Experimental eye research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown plus signaling pathway dissection plus functional cytokine readout, single lab\",\n      \"pmids\": [\"23232207\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Retinoids (naturally occurring and synthetic) directly activate recombinant and native TRPV1 ion channel; in vivo retinoid-induced pain behaviors were eliminated or significantly reduced by genetic or pharmacological inhibition of TRPV1, identifying TRPV1 as an ionotropic receptor for retinoids.\",\n      \"method\": \"Electrophysiology with recombinant TRPV1, TRPV1 knockout mice, pharmacological inhibition, in vivo nociceptive behavioral assays\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — recombinant channel activation plus genetic KO plus pharmacological inhibition, multiple orthogonal methods\",\n      \"pmids\": [\"23925292\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Resolvins (RvD1, RvD2, RvE1) prevent histamine-induced TRPV1 sensitization in DRG neurons; RvD2 reversal of TRPV1 sensitization is blocked by the GPR18 antagonist O-1918 and by pertussis toxin, establishing a GPR18/Gi-dependent pathway through which RvD2 desensitizes TRPV1.\",\n      \"method\": \"Live Ca2+ imaging of DRG neurons, pharmacological antagonism (GPR18, pertussis toxin), in vivo visceral hypersensitivity models\",\n      \"journal\": \"Gut\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Ca2+ imaging plus pharmacological pathway dissection plus in vivo validation, single lab\",\n      \"pmids\": [\"33023902\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PKCε-dependent phosphorylation of TRPV1 at sites T704 and S502 mediates carotid body sensing of asthma-associated Th2 cytokines; site-directed mutagenesis of these residues impaired the response, and systemic PKCε blockade reduced asthmatic bronchoconstriction without affecting oxygen sensing.\",\n      \"method\": \"Site-directed mutagenesis of TRPV1 T704 and S502, patch-clamp, nerve recordings, in situ rat preparations, pharmacological PKCε inhibition, in vivo allergen challenge\",\n      \"journal\": \"The Journal of physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — mutagenesis of specific phosphorylation sites plus electrophysiology plus in vivo functional validation\",\n      \"pmids\": [\"33180962\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"PIP2 directly potentiates TRPV1 in excised inside-out patches; polylysine (a cationic phosphoinositide sequestering agent) inhibited TRPV1 rather than potentiating it, contradicting the proposed tonic inhibition model for PIP2 on TRPV1.\",\n      \"method\": \"Inside-out patch-clamp electrophysiology, direct PIP2 application, polylysine sequestration\",\n      \"journal\": \"The Journal of general physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct reconstitution in inside-out patches with defined lipid application, rigorous controls; reported in same study as PI3K binding (PMID 17074976)\",\n      \"pmids\": [\"17074976\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"TRPV1 activation by capsaicin in SUM149PT triple-negative breast cancer cells induced Ca2+ influx (blocked by capsazepine), caused growth inhibition, and induced apoptosis and necrosis, establishing a functional TRPV1-mediated Ca2+-dependent anti-tumor signaling pathway.\",\n      \"method\": \"Ca2+ imaging, pharmacological inhibition (capsazepine), cell viability and apoptosis assays\",\n      \"journal\": \"Breast cancer (Dove Medical Press)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, pharmacological inhibition only, no molecular mechanism beyond Ca2+ influx established\",\n      \"pmids\": [\"28008282\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Troglitazone activates TRPV1 to cause deacetylation of PPARγ in 3T3-L1 cells; TRPV1 inhibition by capsazepine prevented Troglitazone-induced Ca2+ influx, and inhibition of TRPV1 or Sirtuin 1 prevented PPARγ deacetylation, establishing a TRPV1→Ca2+→Sirtuin1→PPARγ deacetylation pathway.\",\n      \"method\": \"Ca2+ imaging, pharmacological inhibition (capsazepine), TRPV1 overexpression, Western blot for PPARγ acetylation, Sirtuin 1 inhibition\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular basis of disease\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — pharmacological inhibition plus overexpression, single lab, no direct phosphorylation/deacetylation site identified\",\n      \"pmids\": [\"30496795\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TRPV1 and TRPV4 form functional heteromeric channel complexes in retinal microvascular endothelial cells (RMECs), demonstrated by proximity ligation assay and electrophysiological recording; pharmacological inhibition of either channel suppressed in vitro tubulogenesis and reduced retinal neovascularization in the oxygen-induced retinopathy mouse model.\",\n      \"method\": \"Proximity ligation assay, patch-clamp electrophysiology, in vitro angiogenesis assays, oxygen-induced retinopathy mouse model\",\n      \"journal\": \"Investigative ophthalmology & visual science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — PLA plus electrophysiology for heteromer identification plus in vivo functional validation\",\n      \"pmids\": [\"31369032\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"In TRPV1-expressing HEK cells co-expressing the histamine H1 receptor (a PLC-coupled receptor), histamine stimulated 2-arachidonoylglycerol (2-AG) formation via diacylglycerol lipase, and the resulting 2-AG activated TRPV1 currents; this effect was augmented by monoacylglycerol lipase inhibition (JZL184) and abolished by diacylglycerol lipase inhibition, placing 2-AG generation downstream of PLC as a direct TRPV1 activator.\",\n      \"method\": \"Whole-cell patch-clamp, pharmacological enzyme inhibitors, mass spectrometry for 2-AG quantification\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — electrophysiology plus metabolic tracing, single lab, two orthogonal methods\",\n      \"pmids\": [\"24312564\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Ca2+ flowing through TRPV1 activates PLCδ isoforms, resulting in PIP2 depletion that limits TRPV1 channel activity and contributes to capsaicin-induced desensitization; PIP2 acts as a positive cofactor for TRPV1 via direct interaction, and its depletion is a mechanism of desensitization.\",\n      \"method\": \"Excised patch electrophysiology, PIP2 application/depletion experiments, PLCδ pharmacology (reviewed with cited primary data)\",\n      \"journal\": \"Pflugers Archiv : European journal of physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — inside-out patch data plus PLC pathway manipulation, findings from multiple labs synthesized\",\n      \"pmids\": [\"25754030\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TRPV1 is a homotetrameric (or heteromeric with TRPA1/TRPV4) non-selective cation channel that is directly activated by noxious heat (>43°C), protons, capsaicin (binding a transmembrane pocket in a 'tail-up, head-down' configuration that stabilizes the open state via S4-S5 linker contact), endogenous lipids (anandamide, 2-arachidonoylglycerol, monoacylglycerols), retinoids, and peptide toxins; its gating involves sequential conformational changes from intracellular gate opening through selectivity filter dilation; its activity is bidirectionally regulated by plasma membrane PIP2 (positive cofactor whose depletion by Ca2+-activated PLCδ underlies desensitization) and by phosphorylation at multiple sites (including S801 by PKC and S502/T704 by PKCε) scaffolded by AKAP150, which controls sensitization; NGF-mediated sensitization occurs through physical coupling of PI3K-p85β to the TRPV1 N-terminus and consequent PI3K-dependent trafficking of TRPV1 to the plasma membrane; TRPV1 also binds and modulates μ-opioid receptor signaling by triggering Ca2+/calmodulin-dependent GRK5 membrane dissociation (blocking MOR phosphorylation) and by promoting nuclear β-arrestin2 translocation to prevent MOR desensitization; in the CNS, TRPV1 is present at synapses, regulates vesicle recycling, and controls stress responses through a HDAC2-dependent pathway.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TRPV1 is a polymodal, non-selective cation channel that transduces noxious chemical and physical stimuli into nociceptive signaling and serves as a hub for inflammatory sensitization [#0, #6]. Cryo-EM studies establish that protons, vanilloid agonists, and peptide toxins drive selectivity-filter conformational transitions allosterically coupled to the cytoplasmic gate, and that channel opening proceeds as a sequential trajectory—intracellular gate opening, then selectivity filter dilation, then pore-loop rearrangement [#0, #1]. Capsaicin engages a transmembrane pocket in a 'tail-up, head-down' configuration and stabilizes the open state through 'pull-and-contact' with the S4-S5 linker [#2]. Beyond exogenous vanilloids, TRPV1 is directly activated by endogenous lipids, including the diacylglycerol metabolites 2-AG and 1-AG generated downstream of phospholipase C, and by retinoids, defining it as an ionotropic receptor for these ligands [#7, #22, #15]. Channel activity is tuned by membrane PIP2, which acts as a direct positive cofactor whose depletion by Ca2+-activated PLCδ underlies capsaicin desensitization [#18, #23], and by phosphorylation: AKAP150 scaffolds PKA to sensitize the channel [#4], PKC phosphorylation at S801 mediates inflammatory sensitization to ligand [#6], and PKCε phosphorylation at T704/S502 underlies cytokine sensing in the carotid body [#17]. Growth-factor signaling sensitizes TRPV1 through PI3K p85β binding to its N-terminus and consequent trafficking to the plasma membrane [#3, #8]. TRPV1 also assembles into heteromeric channels with TRPA1 and TRPV4 that alter its gating and pharmacology [#5, #21]. Beyond its channel role, TRPV1 modulates μ-opioid receptor signaling by binding MOR1 and blocking GRK5- and β-arrestin2-dependent receptor phosphorylation and desensitization [#9, #10], and in the CNS it localizes to synapses, regulates vesicle recycling, and controls stress responses via a glucocorticoid receptor/HDAC2 pathway [#13, #11].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Established that growth-factor receptor tyrosine kinase signaling sensitizes TRPV1 not only by raising sensitivity but by mobilizing the channel to the plasma membrane, introducing trafficking as a sensitization mechanism.\",\n      \"evidence\": \"Electrophysiology and subcellular fractionation in DRG neurons and heterologous cells with PI3K/PKC inhibitors (insulin/IGF-I)\",\n      \"pmids\": [\"15857517\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct kinase-channel contacts not mapped\", \"Single-lab translocation assay\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Defined a physical mechanism for NGF sensitization by showing PI3K p85β binds the TRPV1 N-terminus to drive surface trafficking, and clarified PIP2 as a direct positive cofactor in excised patches.\",\n      \"evidence\": \"Yeast two-hybrid, reciprocal Co-IP from HEK293 and DRG neurons, in vitro pulldown, TIRF, and inside-out patch-clamp with direct PIP2/polylysine application\",\n      \"pmids\": [\"17074976\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of p85β-N-terminus binding unresolved\", \"How trafficking couples to channel activation not detailed\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Showed TRPV1 has cytoskeletal/morphogenic activity beyond ion conduction, with N- and C-terminal domains driving filopodia initiation and microtubule stabilization.\",\n      \"evidence\": \"Domain-deletion constructs and live imaging in F11, HeLa, and HEK cells\",\n      \"pmids\": [\"17714453\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological relevance in neurons unclear\", \"Mechanism linking channel to myosin upregulation unknown\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identified AKAP150 as the scaffold that targets PKA to TRPV1, providing a structural basis for kinase-dependent sensitization and inflammatory hyperalgesia.\",\n      \"evidence\": \"Co-IP from trigeminal neurons, siRNA knockdown, Ca2+ assay in CHO cells, and in vivo AKAP antagonism\",\n      \"pmids\": [\"18381233\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phosphosites mediating PKA sensitization not defined here\", \"AKAP150 binding interface on TRPV1 unmapped\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Extended TRPV1 function to central synapses, showing presence in synaptic vesicles and rapid modulation of vesicle recycling.\",\n      \"evidence\": \"Synaptosome fractionation, immunocolocalization, and FM4-64 imaging in cortical neurons\",\n      \"pmids\": [\"20483957\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Endogenous synaptic ligand not identified\", \"Single-lab, no genetic confirmation of synaptic role\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified endogenous direct activators of TRPV1—PLC-derived monoacylglycerols and retinoids—broadening the channel's ligand repertoire and linking it to lipid signaling and retinoid-induced pain.\",\n      \"evidence\": \"Inside-out and whole-cell patch-clamp, TRPV1 knockout mice, MAGL inhibition, mass spectrometry; recombinant/native channel activation with retinoids and KO/pharmacology in nociception\",\n      \"pmids\": [\"24312564\", \"23925292\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Binding site for monoacylglycerols/retinoids not structurally defined\", \"Physiological concentrations driving activation in vivo uncertain\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstrated a downstream signaling output of TRPV1 in non-neuronal cells via a TRPV1→p38 MAPK→IL-6 inflammatory axis in corneal fibroblasts.\",\n      \"evidence\": \"siRNA silencing, Ca2+ imaging, patch-clamp, MAPK phospho-assays, IL-6 ELISA\",\n      \"pmids\": [\"23232207\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether this axis operates in vivo not tested\", \"Single-lab cell-line study\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showed TRPV1 forms defined heteromeric channels with TRPA1, altering stoichiometry, agonist sensitivity, and current magnitude.\",\n      \"evidence\": \"Concatemers, atomic force microscopy, patch-clamp, epitope mapping\",\n      \"pmids\": [\"24643480\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Native abundance of TRPV1::TRPA1 heteromers in vivo unclear\", \"Structural basis of functional inhibition by TRPA1 not resolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Consolidated the PIP2/PLCδ feedback model of desensitization, with Ca2+ entry through TRPV1 activating PLCδ to deplete its own positive cofactor PIP2.\",\n      \"evidence\": \"Excised-patch electrophysiology and PLCδ pharmacology synthesized across labs\",\n      \"pmids\": [\"25754030\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Quantitative contribution of PIP2 depletion vs other desensitization routes unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showed that GPCR-evoked PLC signaling activates TRPV1 indirectly through DAG-lipase-generated 2-AG, linking H1 receptor signaling to channel gating.\",\n      \"evidence\": \"Whole-cell patch-clamp, DAGL/MAGL inhibitors, mass spectrometry in HEK cells co-expressing H1R\",\n      \"pmids\": [\"24312564\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab heterologous system\", \"Native cell relevance not established here\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined a non-canonical role for TRPV1 in prolonging opioid analgesia by binding MOR1 and blocking its phosphorylation/desensitization through Ca2+/calmodulin-dependent GRK5 displacement and MAPK-driven nuclear β-arrestin2 sequestration.\",\n      \"evidence\": \"Co-IP, GRK5 localization and phosphorylation assays, β-arrestin2 translocation, TRPV1 KO mice, CFA inflammatory pain model\",\n      \"pmids\": [\"29203659\", \"30940767\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"TRPV1-MOR1 binding interface not mapped\", \"GRK5 mechanism from single lab without reciprocal structural validation\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Linked TRPV1 to central stress regulation through a glucocorticoid receptor/HDAC2 transcriptional pathway, establishing a CNS behavioral output downstream of the channel.\",\n      \"evidence\": \"Trpv1 KO mice, hippocampal siRNA knockdown, HDAC2 overexpression rescue, behavioral stress assays\",\n      \"pmids\": [\"28402861\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How channel activity couples to GR/HDAC2 transcription unknown\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Genetically pinned PKC sensitization to a single residue, showing S801 phosphorylation selectively governs ligand (not heat) sensitization and inflammatory pain in vivo.\",\n      \"evidence\": \"CRISPR S801A knock-in mice, patch-clamp, nocifensive behavior\",\n      \"pmids\": [\"31676602\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Other PKC sites contributing to sensitization not addressed by this mutation\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrated TRPV1::TRPV4 heteromers in vascular endothelium with a functional role in pathological angiogenesis.\",\n      \"evidence\": \"Proximity ligation assay, patch-clamp, angiogenesis assays, oxygen-induced retinopathy model\",\n      \"pmids\": [\"31369032\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Subunit stoichiometry of TRPV1::TRPV4 not resolved\", \"Signaling downstream of heteromer in endothelium unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified PKCε phosphorylation of T704/S502 as the mechanism for carotid-body cytokine sensing, and a GPR18/Gi pathway by which resolvins desensitize TRPV1.\",\n      \"evidence\": \"Site-directed mutagenesis, patch-clamp, nerve recordings, in vivo allergen challenge; DRG Ca2+ imaging with GPR18 antagonist and pertussis toxin\",\n      \"pmids\": [\"33180962\", \"33023902\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How distinct PKC isoforms select sites mechanistically unclear\", \"Resolvin/GPR18 effector linking to channel not defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Resolved the temporal order of TRPV1 gating, showing activation is a concerted stepwise allosteric process from gate to filter.\",\n      \"evidence\": \"Cryo-EM thermal-titration ensemble analysis with RTx plus mutagenesis\",\n      \"pmids\": [\"35610228\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How heat per se drives the same trajectory not directly captured\", \"Lipid cofactor states during transitions not modeled\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the channel's diverse signaling outputs (synaptic, MOR-modulatory, transcriptional/HDAC2, lipid-deacetylation) are mechanistically coupled to ion conduction versus protein-scaffolding functions remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking Ca2+ flux to nuclear/transcriptional outputs\", \"Binding interfaces for most protein partners unmapped\", \"Endogenous activating ligands for central roles unidentified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [0, 1, 2, 5]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 15, 7]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [7, 18, 22, 23]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [0, 15]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3, 8, 18]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [13]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 9, 10, 17]},\n      {\"term_id\": \"R-HSA-9709957\", \"supporting_discovery_ids\": [0, 2, 15]}\n    ],\n    \"complexes\": [\n      \"TRPV1::TRPA1 heteromeric channel\",\n      \"TRPV1::TRPV4 heteromeric channel\"\n    ],\n    \"partners\": [\n      \"PIK3R2 (p85β)\",\n      \"AKAP150\",\n      \"TRPA1\",\n      \"TRPV4\",\n      \"OPRM1 (MOR1)\",\n      \"GRK5\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}