Similar articles

Abstract: transient receptor potential vanilloid subtype 1 (TRPV1), a polymodally activated, calcium-permeable non-selective cation channel, is broadly present in all parts of the body, with notable expression in the nociceptive neurons. Both physiological and pathological functions rely heavily on this ion channel, mediating responses to a variety of stimuli and contributing to the maintenance of bodily homeostasis. Its unique ability to respond to temperature changes, chemical ligands, and voltage fluctuations positions TRPV1 as a key target in understanding and modulating normal bodily functions, in addition to diagnosing and treating diseases. This review synthesizes current knowledge on the structure, gating mechanisms, and physiological and pathological roles of TRPV1, highlighting its potential as a therapeutic target across multiple disease states. By providing a comprehensive overview of the multifaceted functions of TRPV1, this review aims to inform and inspire future research, finally contributing to the advancement of new therapeutic techniques focusing on TRPV1 to enhance human health.

TRPV1：从结构到功能--多维度治疗靶点的研究进展

[1]AbdallaSS, HarbAA, AlmasriIM, et al., 2022. The interaction of TRPV1 and lipids: insights into lipid metabolism. Front Physiol, 13:1066023.

[2]AhernGP, BrooksIM, MiyaresRL, et al., 2005. Extracellular cations sensitize and gate capsaicin receptor TRPV1 modulating pain signaling. J Neurosci, 25(21):5109-5116.

[3]AndreevYA, KozlovSA, KoshelevSG, et al., 2008. Analgesic compound from sea anemone Heteractis crispa is the first polypeptide inhibitor of vanilloid receptor 1 (TRPV1). J Biol Chem, 283(35):23914-23921.

[4]AndreevYA, KozlovSA, KorolkovaYV, et al., 2013. Polypeptide modulators of TRPV1 produce analgesia without hyperthermia. Mar Drugs, 11(12):5100-5115.

[5]AneirosE, CaoLS, PapakostaM, et al., 2011. The biophysical and molecular basis of TRPV1 proton gating. EMBO J, 30(6):994-1002.

[6]AraiT, OhkuriT, YasumatsuK, et al., 2010. The role of transient receptor potential vanilloid-1 on neural responses to acids by the chorda tympani, glossopharyngeal and superior laryngeal nerves in mice. Neuroscience, 165(4):1476-1489.

[7]ArnoldWR, MancinoA, MossIII FR, et al., 2024. Structural basis of TRPV1 modulation by endogenous bioactive lipids. Nat Struct Mol Biol, 31:1377-1385.

[8]AzlanA, SultanaS, HueiCS, et al., 2022. Antioxidant, anti-obesity, nutritional and other beneficial effects of different chili pepper: a review. Molecules, 27(3):898.

[9]BaeC, AnselmiC, KaliaJ, et al., 2016. Structural insights into the mechanism of activation of the TRPV1 channel by a membrane-bound tarantula toxin. eLife, 5:e11273.

[10]BlumbergPM, PearceLV, LeeJ, 2011. TRPV1 activation is not an all-or-none event: TRPV1 partial agonism/antagonism and its regulatory modulation. Curr Top Med Chem, 11(17):2151-2158.

[11]BohlenCJ, PrielA, ZhouS, et al., 2010. A bivalent tarantula toxin activates the capsaicin receptor, TRPV1, by targeting the outer pore domain. Cell, 141(5):834-845.

[12]BrauchiS, OrtaG, SalazarM, et al., 2006. A hot-sensing cold receptor: C-terminal domain determines thermosensation in transient receptor potential channels. J Neurosci, 26(18):4835-4840.

[13]CaoEH, Cordero-MoralesJF, LiuBY, et al., 2013a. TRPV1 channels are intrinsically heat sensitive and negatively regulated by phosphoinositide lipids. Neuron, 77(4):667-679.

[14]CaoEH, LiaoMF, ChengYF, et al., 2013b. TRPV1 structures in distinct conformations reveal activation mechanisms. Nature, 504:113-118.

[15]CaoT, HoCT, WangWS, et al., 2025. Capsaicin mitigates Reverbα-involved lipid metabolism disorder in HepG2 cells and obese mice through a Trpv1-dependent mechanism. J Agric Food Chem, 73(9):5300-5310.

[16]CaoX, MaLL, YangF, et al., 2014. Divalent cations potentiate TRPV1 channel by lowering the heat activation threshold. J Gen Physiol, 143(1):75-90.

[17]CaterinaMJ, SchumacherMA, TominagaM, et al., 1997. The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature, 389:816-824.

[18]CaterinaMJ, LefflerA, MalmbergAB, et al., 2000. Impaired nociception and pain sensation in mice lacking the capsaicin receptor. Science, 288(5464):306-313.

[19]ChenB, HuZT, ChenXL, et al., 2024. Molecular mechanisms of two novel and selective TRPV1 channel activators. Int J Biol Macromol, 275(Pt 1):133658.

[20]ChengJJ, ZengML, PengBW, et al., 2024. Transient receptor potential vanilloid-1 (TRPV1) channels act as suppressors of the growth of glioma. Brain Res Bull, 211:110950.

[21]ChibaT, MasukoS, KawanoH, 1986. Correlation of mitochondrial swelling after capsaicin treatment and substance P and somatostatin immunoreactivity in small neurons of dorsal root ganglion in the rat. Neurosci Lett, 64(3):311-316.

[22]ChouMZ, MtuiT, GaoYD, et al, 2004. Resiniferatoxin binds to the capsaicin receptor (TRPV1) near the extracellular side of the S4 transmembrane domain. Biochemistry, 43(9):2501-2511.

[23]ClaphamDE, MillerC, 2011. A thermodynamic framework for understanding temperature sensing by transient receptor potential (TRP) channels. Proc Natl Acad Sci USA, 108(49):19492-19497.

[24]de la RocheJ, WaltherI, LeonowW, et al., 2016. Lactate is a potent inhibitor of the capsaicin receptor TRPV1. Sci Rep, 6:36740.

[25]DendaS, DendaM, InoueK, et al., 2010. Glycolic acid induces keratinocyte proliferation in a skin equivalent model via TRPV1 activation. J Dermatol Sci, 57(2):108-113.

[26]DengF, ZhaoBC, YangX, et al., 2021. The gut microbiota metabolite capsiate promotes Gpx4 expression by activating TRPV1 to inhibit intestinal ischemia reperfusion-induced ferroptosis. Gut Microbes, 13(1):1902719.

[27]DerryS, MooreRA, 2012. Topical capsaicin (low concentration) for chronic neuropathic pain in adults. Cochrane Database Syst Rev, 2012(9):CD010111.

[28]DerryS, RiceASC, ColeP, et al., 2017. Topical capsaicin (high concentration) for chronic neuropathic pain in adults. Cochrane Database Syst Rev, 1(1):CD007393.

[29]ElokelyK, VelisettyP, DelemotteL, et al., 2016. Understanding TRPV1 activation by ligands: insights from the binding modes of capsaicin and resiniferatoxin. Proc Natl Acad Sci USA, 113(2):E137-E145.

[30]FakihD, Guerrero-MorenoA, BaudouinC, et al., 2021. Capsazepine decreases corneal pain syndrome in severe dry eye disease. J Neuroinflammation, 18:111.

[31]FanJP, KeH, LeiJ, et al., 2024. Structural basis of TRPV1 inhibition by SAF312 and cholesterol. Nat Commun, 15:6689.

[32]FreynhagenR, BaronR, HuygenF, et al., 2025. Narrative review of the efficacy and safety of the high-concentration (179 mg) capsaicin patch in peripheral neuropathic pain with recommendations for clinical practice and future research. PAIN Rep, 10(2):e1235.

[33]GaoNN, YangF, ChenSY, et al., 2020. The role of TRPV1 ion channels in the suppression of gastric cancer development. J Exp Clin Cancer Res, 39:206.

[34]GaoY, CaoEH, JuliusD, et al., 2016. TRPV1 structures in nanodiscs reveal mechanisms of ligand and lipid action. Nature, 534:347-351.

[35]GaoZS, YanXZ, Wang-SattlerR, et al., 2025. Metabolomics reveals reasons for the efficacy of acupuncture in migraine patients: the role of anaerobic glycolysis and mitochondrial citrate in migraine relief. Phenomics, online.

[36]GaramiA, ShimanskyYP, RumbusZ, et al., 2020. Hyperthermia induced by transient receptor potential vanilloid-1 (TRPV1) antagonists in human clinical trials: insights from mathematical modeling and meta-analysis. Pharmacol Ther, 208:107474.

[37]GouinO, L'HerondelleK, LebonvalletN, et al., 2017. TRPV1 and TRPA1 in cutaneous neurogenic and chronic inflammation: pro-inflammatory response induced by their activation and their sensitization. Protein Cell, 8(9):644-661.

[38]GrandlJ, KimSE, UzzellV, et al., 2010. Temperature-induced opening of TRPV1 ion channel is stabilized by the pore domain. Nat Neurosci, 13:708-714.

[39]GunthorpeMJ, RamiHK, JermanJC, et al., 2004. Identification and characterisation of SB-366791, a potent and selective vanilloid receptor (VR1/TRPV1) antagonist. Neuropharmacology, 46:133-149.

[40]HaltiaT, FreireE, 1995. Forces and factors that contribute to the structural stability of membrane proteins. Biochim Biophys Acta Rev Biomembr, 1241(2):295-322.

[41]HofmannNA, BarthS, Waldeck-WeiermairM, et al., 2014. TRPV1 mediates cellular uptake of anandamide and thus promotes endothelial cell proliferation and network-formation. Biol Open, 3(12):1164-1172.

[42]HolzerP, 1988. Local effector functions of capsaicin-sensitive sensory nerve endings: involvement of tachykinins, calcitonin gene-related peptide and other neuropeptides. Neuroscience, 24(3):739-768.

[43]HolzerP, 1991. Capsaicin: cellular targets, mechanisms of action, and selectivity for thin sensory neurons. Pharmacol Rev, 43(2):143-201.

[44]HouNY, HeXL, YangYH, et al., 2019. TRPV1 induced apoptosis of colorectal cancer cells by activating calcineurin-NFAT2-p53 signaling pathway. Biomed Res Int, 2019:6712536.

[45]HuF, SunWW, ZhaoXT, et al., 2008. TRPV1 mediates cell death in rat synovial fibroblasts through calcium entry-dependent ROS production and mitochondrial depolarization. Biochem Biophys Res Commun, 369(4):989-993.

[46]JambrinaE, AlonsoR, AlcaldeM, et al., 2003. Calcium influx through receptor-operated channel induces mitochondria-triggered paraptotic cell death. J Biol Chem, 278(16):14134-14145.

[47]JiangXH, WangCH, KeZL, et al., 2022. The ion channel TRPV1 gain-of-function reprograms the immune microenvironment to facilitate colorectal tumorigenesis. Cancer Lett, 527:95-106.

[48]JordtSE, JuliusD, 2002. Molecular basis for species-specific sensitivity to “hot” chili peppers. Cell, 108(3):421-430.

[49]JordtSE, TominagaM, JuliusD, 2000. Acid potentiation of the capsaicin receptor determined by a key extracellular site. Proc Natl Acad Sci USA, 97(14):8134-8139.

[50]KangMS, LeeGH, ChoiGE, et al., 2020. Neuroprotective effect of Nypa fruticans wurmb by suppressing TRPV1 following sciatic nerve crush injury in a rat. Nutrients, 12(9):2618.

[51]KitaharaT, LiHS, BalabanCD, 2005. Changes in transient receptor potential cation channel superfamily V (TRPV) mRNA expression in the mouse inner ear ganglia after kanamycin challenge. Hear Res, 201(1-2):132-144.

[52]KleinRM, Ufret-VincentyCA, HuaL, et al., 2008. Determinants of molecular specificity in phosphoinositide regulation: PHOSPHATIDYLINOSITOL (4,5)-BISPHOSPHATE (PI(4,5)P₂) IS THE ENDOGENOUS LIPID REGULATING TRPV1. J Biol Chem, 283(38):26208-26216.

[53]KnappO, McArthurJR, AdamsDJ, 2012. Conotoxins targeting neuronal voltage-gated sodium channel subtypes: potential analgesics? Toxins, 4(11):1236-1260.

[54]KongWL, PengYY, PengBW, 2017. Modulation of neuroinflammation: role and therapeutic potential of TRPV1 in the neuro-immune axis. Brain Behav Immun, 64:354-366.

[55]KornilovP, PeretzA, LeeY, et al., 2014. Promiscuous gating modifiers target the voltage sensor of K_v7.2, TRPV1, and H_v1 cation channels. FASEB J, 28(6):2591-2602.

[56]KwonDH, ZhangF, SuoY, et al., 2021. Heat-dependent opening of TRPV1 in the presence of capsaicin. Nat Struct Mol Biol, 28:554-563.

[57]KwonDH, ZhangF, FedorJG, et al., 2022. Vanilloid-dependent TRPV1 opening trajectory from cryoem ensemble analysis. Nat Commun, 13:2874.

[58]Ladrón-de-GuevaraE, DominguezL, Rangel-YescasGE, et al., 2020. The contribution of the ankyrin repeat domain of TRPV1 as a thermal module. Biophys J, 118(4):836-845.

[59]LapointeTK, BassoL, IftincaMC, et al., 2015. TRPV1 sensitization mediates postinflammatory visceral pain following acute colitis. Am J Physiol Gastrointest Liver Physiol, 309(2):G87-G99.

[60]LeoM, SchulteM, SchmittLI, et al., 2017. Intrathecal resiniferatoxin modulates TRPV1 in DRG neurons and reduces TNF-induced pain-related behavior. Mediators Inflamm, 2017:2786427.

[61]LiaoMF, CaoEH, JuliusD, et al., 2013. Structure of the TRPV1 ion channel determined by electron cryo-microscopy. Nature, 504:107-112.

[62]LiuBY, HuiK, QinF, 2003. Thermodynamics of heat activation of single capsaicin ion channels VR1. Biophys J, 85(5):2988-3006.

[63]LiuJ, HuangSY, YuRX, et al., 2022. TRPV1⁺ sensory nerves modulate corneal inflammation after epithelial abrasion via RAMP1 and SSTR5 signaling. Mucosal Immunol, 15(5):867-881.

[64]LiuT, WangG, TaoHH, et al., 2016. Capsaicin mediates caspases activation and induces apoptosis through P38 and JNK MAPK pathways in human renal carcinoma. BMC Cancer, 16:790.

[65]LuW, LiJ, GongLP, et al., 2014. H₂S modulates duodenal motility in male rats via activating TRPV1 and K_ATP channels. Br J Pharmacol, 171(6):1534-1550.

[66]LuoZD, MaLQ, ZhaoZG, et al., 2012. TRPV1 activation improves exercise endurance and energy metabolism through PGC-1α upregulation in mice. Cell Res, 22(3):551-564.

[67]LyallV, HeckGL, VinnikovaAK, et al., 2004. The mammalian amiloride‐insensitive non‐specific salt taste receptor is a vanilloid receptor‐1 variant. J Physiol, 558:147-159.

[68]Marek-JozefowiczL, NedoszytkoB, GrochockaM, et al., 2023. Molecular mechanisms of neurogenic inflammation of the skin. Int J Mol Sci, 24(5):5001.

[69]MatsumotoK, KurosawaE, TeruiH, et al., 2009. Localization of TRPV1 and contractile effect of capsaicin in mouse large intestine: high abundance and sensitivity in rectum and distal colon. Am J Physiol Gastrointest Liver Physiol, 297(2):G348-G360.

[70]MattaJA, AhernGP, 2007. Voltage is a partial activator of rat thermosensitive TRP channels. J Physiol, 585(2):469-482.

[71]MazetoTK, PicadaJN, CorreaÁP, et al., 2020. Antinociceptive and genotoxic assessments of the antagonist TRPV1 receptor SB-366791 on morphine-induced tolerance in mice. Naunyn Schmiedeberg’s Arch Pharmacol, 393(3):481-490.

[72]Moiseenkova-BellVY, StanciuLA, SeryshevaII, et al., 2008. Structure of TRPV1 channel revealed by electron cryomicroscopy. Proc Natl Acad Sci USA, 105(21):7451-7455.

[73]MontellC, BirnbaumerL, FlockerziV, et al., 2002. A unified nomenclature for the superfamily of TRP cation channels. Mol Cell, 9(2):229-231.

[74]MoroniM, Servin-VencesMR, FleischerR, et al., 2018. Voltage gating of mechanosensitive PIEZO channels. Nat Commun, 9:1096.

[75]MugoA, ChouRY, ChinF, et al., 2023. A suicidal mechanism for the exquisite temperature sensitivity of TRPV1. Proc Natl Acad Sci USA, 120(36):e2300305120.

[76]NadezhdinKD, NeubergerA, NikolaevYA, et al., 2021. Extracellular cap domain is an essential component of the TRPV1 gating mechanism. Nat Commun, 12:2154.

[77]NeubergerA, OdaM, NikolaevYA, et al., 2023. Human TRPV1 structure and inhibition by the analgesic SB-366791. Nat Commun, 14:2451.

[78]NieRF, LiuQ, WangXS, 2022. TRPV1 is a potential tumor suppressor for its negative association with tumor proliferation and positive association with antitumor immune responses in pan-cancer. J Oncol, 2022:6964550.

[79]NLM, 2009. Resiniferatoxin to treat severe pain associated with advanced cancer. https://clinicaltrials.gov/study/NCT00804154

[80]NLM, 2020. A phase 3 study to evaluate the efficacy and safety of resiniferatoxin for pain due to osteoarthritis of the knee. https://clinicaltrials.gov/study/NCT04044742

[81]NLM, 2021. Pleiotropic role of TRPV1 in psoriasis inflammation (TRIP). https://clinicaltrials.gov/study/NCT04848194

[82]OliveiraSM, SilvaCR, TrevisanG, et al., 2016. Antinociceptive effect of a novel armed spider peptide Tx3-5 in pathological pain models in mice. Pflugers Arch Eur J Physiol, 468(5):881-894.

[83]O'NeillJ, BrockC, OlesenAE, et al., 2012. Unravelling the mystery of capsaicin: a tool to understand and treat pain. Pharmacol Rev, 64(4):939-971.

[84]OtzenD, 2014. Membrane protein folding and stability. Arch Biochem Biophys, 564:262-264.

[85]Öz-ArslanD, YavuzM, KanB, 2024. Exploring orphan GPCRs in neurodegenerative diseases. Front Pharmacol, 15:1394516.

[86]PayritsM, ZsidóBZ, Nehr-MajorosAK, et al., 2024. Lipid raft disruption inhibits the activation of transient receptor potential vanilloid 1, but not TRP Melastatin 3 and the voltage-gated L-type calcium channels in sensory neurons. Front Cell Dev Biol, 12:1452306.

[87]PintérE, HelyesZ, SzőkeÉ, et al., 2023. The triple function of the capsaicin-sensitive sensory neurons: in memoriam János Szolcsányi. Temperature, 10(1):13-34.

[88]PremkumarLS, 2010. Targeting TRPV1 as an alternative approach to narcotic analgesics to treat chronic pain conditions. AAPS J, 12(3):361-370.

[89]RieraCE, HuisingMO, FollettP, et al., 2014. TRPV1 pain receptors regulate longevity and metabolism by neuropeptide signaling. Cell, 157(5):1023-1036.

[90]RosenbaumT, AwayaM, GordonSE, 2002. Subunit modification and association in VR1 ion channels. BMC Neurosci, 3:4.

[91]RowbothamMC, NothaftW, DuanRW, et al., 2011. Oral and cutaneous thermosensory profile of selective TRPV1 inhibition by ABT-102 in a randomized healthy volunteer trial. Pain, 152(5):1192-1200.

[92]SakamotoK, KurokiT, OkunoY, et al., 2014. Activation of the TRPV1 channel attenuates N-methyl-d-aspartic acid-induced neuronal injury in the rat retina. Eur J Pharmacol, 733:13-22.

[93]SałatK, JakubowskaA, KuligK, 2014. Zucapsaicin for the treatment of neuropathic pain. Expert Opin Investig Drugs, 23(10):1433-1440.

[94]SánchezMG, SánchezAM, ColladoB, et al., 2005. Expression of the transient receptor potential vanilloid 1 (TRPV1) in LNCaP and PC-3 prostate cancer cells and in human prostate tissue. Eur J Pharmacol, 515(1-3):20-27.

[95]SappingtonRM, SidorovaT, LongDJ, et al., 2009. TRPV1: contribution to retinal ganglion cell apoptosis and increased intracellular Ca²⁺ with exposure to hydrostatic pressure. Invest Ophthalmol Vis Sci, 50(2):717-728.

[96]SeabrookGR, SuttonKG, JarolimekW, et al., 2002. Functional properties of the high-affinity TRPV1 (VR1) vanilloid receptor antagonist (4-hydroxy-5-iodo-3-methoxyphenylacetate ester) iodo-resiniferatoxin. J Pharmacol Exp Ther, 303(3):1052-1060.

[97]SendelM, DunstA, ForstenpointnerJ, et al., 2023. Capsaicin treatment in neuropathic pain: axon reflex vasodilatation after 4 weeks correlates with pain reduction. Pain, 164(3):534-542.

[98]SendetskiM, WedelS, FurutaniK, et al., 2024. Oleic acid released by sensory neurons inhibits TRPV1-mediated thermal hypersensitivity via GPR40. iScience, 27(8):110552.

[99]SenningEN, CollinsMD, StratiievskaA, et al., 2014. Regulation of TRPV1 ion channel by phosphoinositide (4,5)-bisphosphate. J Biol Chem, 289(16):10999-11006.

[100]ShamsiF, PiperM, HoLL, et al., 2021. Vascular smooth muscle-derived TRPV1⁺ progenitors are a source of cold-induced thermogenic adipocytes. Nat Metab, 3:485-495.

[101]ShirakawaH, YamaokaT, SanpeiK, et al., 2008. TRPV1 stimulation triggers apoptotic cell death of rat cortical neurons. Biochem Biophys Res Commun, 377(4):1211-1215.

[102]SiemensJ, ZhouS, PiskorowskiR, et al., 2006. Spider toxins activate the capsaicin receptor to produce inflammatory pain. Nature, 444:208-212.

[103]SilvestriC, di MarzoV, 2013. The endocannabinoid system in energy homeostasis and the etiopathology of metabolic disorders. Cell Metab, 17(4):475-490.

[104]SintsovaO, GladkikhI, KlimovichA, et al., 2021. TRPV1 blocker HCRG21 suppresses TNF-α production and prevents the development of edema and hypersensitivity in carrageenan-induced acute local inflammation. Biomedicines, 9(7):716.

[105]Sosa-PagánJO, IversenES, GrandlJ, 2017. TRPV1 temperature activation is specifically sensitive to strong decreases in amino acid hydrophobicity. Sci Rep, 7:549.

[106]StockK, KumarJ, SynowitzM, et al., 2012. Neural precursor cells induce cell death of high-grade astrocytomas through stimulation of TRPV1. Nat Med, 18:1232-1238.

[107]SultanaA, SinglaRK, HeXF, et al., 2021. Topical capsaicin for the treatment of neuropathic pain. Curr Drug Metab, 22(3):198-207.

[108]SunJX, ZhuKY, WangYM, et al., 2023. Activation of TRPV1 receptor facilitates myelin repair following demyelination via the regulation of microglial function. Acta Pharmacol Sin, 44(4):766-779.

[109]SunZW, HanJ, ZhaoWT, et al., 2014. TRPV1 activation exacerbates hypoxia/reoxygenation-induced apoptosis in H9C2 cells via calcium overload and mitochondrial dysfunction. Int J Mol Sci, 15(10):18362-18380.

[110]SwansonDM, DubinAE, ShahC, et al., 2005. Identification and biological evaluation of 4-(3-trifluoromethylpyridin-2-yl)piperazine-1-carboxylic acid (5-trifluoromethylpyridin-2-yl)amide, a high affinity TRPV1 (VR1) vanilloid receptor antagonist. J Med Chem, 48(6):1857-1872.

[111]SzallasiA, 2023. Resiniferatoxin: nature’s precision medicine to silence TRPV1-positive afferents. Int J Mol Sci, 24(20):15042.

[112]SzallasiA, 2024. Targeting TRPV1 for cancer pain relief: can it work? Cancers, 16(3):648.

[113]SzolcsányiJ, Jancsó-GáborA, 1975. Sensory effects of capsaicin congeners I. Relationship between chemical structure and pain-producing potency of pungent agents. Arzneimittelforschung, 25(12):1877-1881.

[114]SzolcsányiJ, SándorZ, 2012. Multisteric TRPV1 nocisensor: a target for analgesics. Trends Pharmacol Sci, 33(12):646-655.

[115]TanakaM, HayakawaK, OgawaN, et al., 2020. Structure determination of the human TRPV1 ankyrin-repeat domain under nonreducing conditions. Acta Crystallogr F Struct Biol Commun, 76(Pt 3):130-137.

[116]TominagaM, CaterinaMJ, MalmbergAB, et al., 1998. The cloned capsaicin receptor integrates multiple pain-producing stimuli. Neuron, 21(3):531-543.

[117]TsaiST, WeiTH, YangYW, et al., 2021. Transient receptor potential V1 modulates neuroinflammation in Parkinson’s disease dementia: molecular implications for electroacupuncture and rivastigmine. Iran J Basic Med Sci, 24(10):1336-1345.

[118]TsvetkovEA, PotatievaNN, BolshakovKV, 2017. Voltage-dependent interaction of capsaicine and protons on TRPV1-receptors. Acta Naturae, 9(1):75-80.

[119]ValdesAM, de WildeG, DohertySA, et al., 2011. The Ile585Val TRPV1 variant is involved in risk of painful knee osteoarthritis. Ann Rheum Dis, 70(9):1556-1561.

[120]VercelliC, BarberoR, CunibertiB, et al., 2015. Expression and functionality of TRPV1 receptor in human MCF-7 and canine CF.41 cells. Vet Comp Oncol, 13(2):133-142.

[121]VlachováV, TeisingerJ, SušánkováK, et al., 2003. Functional role of C-terminal cytoplasmic tail of rat vanilloid receptor 1. J Neurosci, 23(4):1340-1350.

[122]VoetsT, DroogmansG, WissenbachU, et al., 2004. The principle of temperature-dependent gating in cold- and heat-sensitive TRP channels. Nature, 430:748-754.

[123]VoightEA, GomtsyanAR, DaanenJF, et al., 2014. Discovery of (R)-1-(7-chloro-2,2-bis(fluoromethyl)chroman-4-yl)-3-(3-methylisoquinolin-5-yl)urea (A-1165442): a temperature-neutral transient receptor potential vanilloid-1 (TRPV1) antagonist with analgesic efficacy. J Med Chem, 57(17):7412-7424.

[124]WangCF, LuJ, ShaXD, et al., 2023. TRPV1 regulates ApoE4-disrupted intracellular lipid homeostasis and decreases synaptic phagocytosis by microglia. Exp Mol Med, 55(2):347-363.

[125]WangWX, SunT, 2023. Impact of TRPV1 on pathogenesis and therapy of neurodegenerative diseases. Molecules, 29:181.

[126]WangY, ZhangY, OuyangJ, et al., 2024. TRPV1 inhibition suppresses non-small cell lung cancer progression by inhibiting tumour growth and enhancing the immune response. Cell Oncol, 47(3):779-791.

[127]WatsonPNC, EvansRJ, 1992. The postmastectomy pain syndrome and topical capsaicin: a randomized trial. Pain, 51(3):375-379.

[128]WoodJN, WinterJ, JamesIF, et al., 1988. Capsaicin-induced ion fluxes in dorsal root ganglion cells in culture. J Neurosci, 8(9):3208-3220.

[129]XuMM, ZhangYB, WangMY, et al., 2019. TRPV1 and TRPA1 in lung inflammation and airway hyperresponsiveness induced by fine particulate matter (PM_2.5). Oxid Med Cell Longev, 2019:7450151.

[130]YangF, CuiYY, WangKW, et al., 2010. Thermosensitive TRP channel pore turret is part of the temperature activation pathway. Proc Natl Acad Sci USA, 107(15):7083-7088.

[131]YangF, MaLL, CaoX, et al., 2014. Divalent cations activate TRPV1 through promoting conformational change of the extracellular region. J Gen Physiol, 143(1):91-103.

[132]YangF, XiaoX, ChengW, et al., 2015. Structural mechanism underlying capsaicin binding and activation of the TRPV1 ion channel. Nat Chem Biol, 11:518-524.

[133]YangF, XuLZ, LeeBH, et al., 2020. An unorthodox mechanism underlying voltage sensitivity of TRPV1 ion channel. Adv Sci, 7(20):2000575.

[134]YangSL, YangF, WeiNN, et al., 2015. A pain-inducing centipede toxin targets the heat activation machinery of nociceptor TRPV1. Nat Commun, 6:8297.

[135]YangY, GuXK, WengWJ, et al., 2024. Correction: SUMOylation-induced membrane localization of TRPV1 suppresses proliferation and migration in gastric cancer cells. Cell Commun Signal, 22:479.

[136]YangYQ, GuoWN, MaJJ, et al., 2018. Downregulated TRPV1 expression contributes to melanoma growth via the calcineurin-ATF3-p53 pathway. J Invest Dermatol, 138(10):2205-2215.

[137]YaoJ, LiuBY, QinF, 2010. Kinetic and energetic analysis of thermally activated TRPV1 channels. Biophys J, 99(6):1743-1753.

[138]YekkiralaAS, RobersonDP, BeanBP, et al., 2017. Breaking barriers to novel analgesic drug development. Nat Rev Drug Discov, 16:545-564.

[139]YoshidaA, FurubeE, MannariT, et al., 2016. TRPV1 is crucial for proinflammatory STAT3 signaling and thermoregulation-associated pathways in the brain during inflammation. Sci Rep, 6:26088.

[140]ZhangF, Jara-OsegueraA, ChangTH, et al., 2018. Heat activation is intrinsic to the pore domain of TRPV1. Proc Natl Acad Sci USA, 115(2):E317-E324.

[141]ZhangKH, JuliusD, ChengYF, 2021. Structural snapshots of TRPV1 reveal mechanism of polymodal functionality. Cell, 184(20):5138-5150.e12.

[142]ZhangH, WangJ, YangF, 2024. Design, synthesis and functional validation of peptide inhibitors based on TRPV1 ion channel agonist RhTx. J Zhejiang Univ (Med Sci), 53(2):201-207 (in Chinese).

[143]ZhangYH, HouBH, LiangPY, et al., 2021. TRPV1 channel mediates NLRP3 inflammasome-dependent neuroinflammation in microglia. Cell Death Dis, 12(12):1159.

[144]ZhangZM, WuXL, ZhangLW, et al., 2020. Menthol relieves acid reflux inflammation by regulating TRPV1 in esophageal epithelial cells. Biochem Biophys Res Commun, 525(1):113-120.

[145]ZhaoLM, ZhangXY, KuangHY, et al., 2013. Effect of TRPV1 channel on the proliferation and apoptosis in asthmatic rat airway smooth muscle cells. Exp Lung Res, 39(7):283-294.

[146]ZhuC, WangMY, GuoJ, et al., 2022. Angelica dahurica extracts attenuate CFA-induced inflammatory pain via TRPV1 in mice. Evid Based Complement Alternat Med, 2022:4684830.

[147]ZhuH, WangY, HeYB, et al., 2022. Inflammation-mediated macrophage polarization induces TRPV1/TRPA1 heteromers in endometriosis. Am J Transl Res, 14(5):3066-3078.