Endocannabinoid activation of the TRPV1 ion channel is distinct from activation by capsaicin

Abstract

Transient receptor potential vanilloid 1 (TRPV1) ion channel serves as the detector for noxious temperature above 42 °C, pungent chemicals like capsaicin, and acidic extracellular pH. This channel has also been shown to function as an ionotropic cannabinoid receptor. Despite the solving of high-resolution three-dimensional structures of TRPV1, how endocannabinoids such as anandamide and N-arachidonoyl dopamine bind to and activate this channel remains largely unknown. Here we employed a combination of patch-clamp recording, site-directed mutagenesis, and molecular docking techniques to investigate how the endocannabinoids structurally bind to and open the TRPV1 ion channel. We found that these endocannabinoid ligands bind to the vanilloid-binding pocket of TRPV1 in the “tail-up, head-down” configuration, similar to capsaicin; however, there is a unique interaction with TRPV1 Y512 residue critical for endocannabinoid activation of TRPV1 channels. These data suggest that a differential structural mechanism is involved in TRPV1 activation by endocannabinoids compared with the classic agonist capsaicin. Transient receptor potential vanilloid 1 (TRPV1) ion channel serves as the detector for noxious temperature above 42 °C, pungent chemicals like capsaicin, and acidic extracellular pH. This channel has also been shown to function as an ionotropic cannabinoid receptor. Despite the solving of high-resolution three-dimensional structures of TRPV1, how endocannabinoids such as anandamide and N-arachidonoyl dopamine bind to and activate this channel remains largely unknown. Here we employed a combination of patch-clamp recording, site-directed mutagenesis, and molecular docking techniques to investigate how the endocannabinoids structurally bind to and open the TRPV1 ion channel. We found that these endocannabinoid ligands bind to the vanilloid-binding pocket of TRPV1 in the “tail-up, head-down” configuration, similar to capsaicin; however, there is a unique interaction with TRPV1 Y512 residue critical for endocannabinoid activation of TRPV1 channels. These data suggest that a differential structural mechanism is involved in TRPV1 activation by endocannabinoids compared with the classic agonist capsaicin. Transient receptor potential vanilloid 1 (TRPV1) ion channel is a nociceptor highly expressed in sensory neurons (1Caterina M.J. Schumacher M.A. Tominaga M. Rosen T.A. Levine J.D. Julius D. The capsaicin receptor: A heat-activated ion channel in the pain pathway.Nature. 1997; 389: 816-824Crossref PubMed Scopus (6707) Google Scholar). As a nonselective cation channel and polymodal receptor, activation of TRPV1 by a plethora of stimuli such as noxious heat, capsaicin, extracellular protons and divalent cations, as well as peptide toxins from venomous animals lead to influx of cations, membrane depolarization, and eventually the sensation of pain (2Julius D. TRP channels and pain.Annu. Rev. Cell Dev. Biol. 2013; 29: 355-384Crossref PubMed Scopus (625) Google Scholar). Therefore, the TRPV1 channel has been pursued as a target for antinociception. However, compounds targeting TRPV1 channel inhibition have failed in clinical trials, as they elicited adverse side effects such as body temperature elevation and impairment of noxious heat sensation (3Kort M.E. Kym P.R. TRPV1 antagonists: Clinical setbacks and prospects for future development.Prog. Med. Chem. 2012; 51: 57-70Crossref PubMed Scopus (51) Google Scholar, 4Gavva N.R. Setbacks in the clinical development of TRPV1 antagonists.Open Drug Discov. J. 2009; 1: 1-35Crossref Google Scholar). Thus, the ligand-gated mechanisms of TRPV1 activation remain to be further elucidated. Besides being activated by external ligand such as capsaicin, TRPV1 channel is also activated by endogenous agonists such as anandamide (AEA), N-arachidonoyl dopamine (NADA), N-oleoylethanolamine (OEA), and N-oleoyldopamine (OLDA). Interestingly, all these ligands are endocannabinoids. The endocannabinoid system is a lipid signaling network widely distributed in the body of all vertebrates, regulating important physiological processes such as energy homeostasis, memory extinction, inflammation, and pain sensation. In particular, previous studies have demonstrated that cannabinoids, such as AEA and Δ9-tetrahydrocannabinol, exert antinociceptive effects in rhesus monkeys (5Donvito G. Nass S.R. Wilkerson J.L. Curry Z.A. Schurman L.D. Kinsey S.G. Lichtman A.H. The endogenous cannabinoid system: A budding source of targets for treating inflammatory and neuropathic pain.Neuropsychopharmacology. 2018; 43: 52-79Crossref PubMed Scopus (126) Google Scholar, 6Manning B.H. Merin N.M. Meng I.D. Amaral D.G. Reduction in opioid- and cannabinoid-induced antinociception in rhesus monkeys after bilateral lesions of the amygdaloid complex.J. Neurosci. 2001; 21: 8238-8246Crossref PubMed Google Scholar). Although two G protein–coupled receptors CB1 and CB2 have been identified as the major cannabinoid receptors (7Howlett A.C. The cannabinoid receptors.Prostaglandins Other Lipid Mediat. 2002; 68-69: 619-631Crossref PubMed Scopus (360) Google Scholar), many TRP channels, including TRPV1, have been recognized as ionotropic cannabinoid receptors (8Di Marzo V. Blumberg P.M. Szallasi A. Endovanilloid signaling in pain.Curr. Opin. Neurobiol. 2002; 12: 372-379Crossref PubMed Scopus (239) Google Scholar, 9Akopian A.N. Ruparel N.B. Jeske N.A. Patwardhan A. Hargreaves K.M. Role of ionotropic cannabinoid receptors in peripheral antinociception and antihyperalgesia.Trends Pharmacol. Sci. 2009; 30: 79-84Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar). Therefore, elucidating mechanisms underlying endocannabinoid binding and activation of TRPV1 will not only help reveal the ligand gating mechanisms of this channel in vivo but also advance the development of antinociceptive drugs targeting TRPV1 and the endocannabinoid system. Endocannabinoids like AEA and NADA and capsaicin share similarities in their chemical structures, as they all have a polar “Head” with hydroxyl group(s), an amide “Neck,” and a “Tail” made of aliphatic chain (Fig. 1, A and B). Based on the three-dimensional structures of the TRPV1 channel (10Gao Y. Cao E. Julius D. Cheng Y. TRPV1 structures in nanodiscs reveal mechanisms of ligand and lipid action.Nature. 2016; 534: 347-351Crossref PubMed Scopus (464) Google Scholar, 11Liao M. Cao E. Julius D. Cheng Y. Structure of the TRPV1 ion channel determined by electron cryo-microscopy.Nature. 2013; 504: 107-112Crossref PubMed Scopus (1049) Google Scholar, 12Cao E. Liao M. Cheng Y. Julius D. TRPV1 structures in distinct conformations reveal activation mechanisms.Nature. 2013; 504: 113-118Crossref PubMed Scopus (656) Google Scholar), our previous studies have shown that capsaicin binds to the vanilloid-binding pocket (VBP) formed by S3, S4 transmembrane helices and S4-S5 linker with a “tail-up, head-down” configuration (13Yang F. Xiao X. Cheng W. Yang W. Yu P. Song Z. Yarov-Yarovoy V. Zheng J. Structural mechanism underlying capsaicin binding and activation of the TRPV1 ion channel.Nat. Chem. Biol. 2015; 11: 518-524Crossref PubMed Scopus (168) Google Scholar), which further imitates a conformational wave to open this channel (14Yang F. Xiao X. Lee B.H. Vu S. Yang W. Yarov-Yarovoy V. Zheng J. The conformational wave in capsaicin activation of transient receptor potential vanilloid 1 ion channel.Nat. Commun. 2018; 9: 2879Crossref PubMed Scopus (32) Google Scholar). However, how endocannabinoids bind to and activate the TRPV1 channel remains largely unknown. Molecular dynamic simulation suggests that AEA may bind to either the cavity formed between S1 and S4 helices or the capsaicin-binding pocket in the TRPV1 channel (15Muller C. Lynch D.L. Hurst D.P. Reggio P.H. A closer look at anandamide interaction with TRPV1.Front. Mol. Biosci. 2020; 7: 144Crossref PubMed Scopus (9) Google Scholar), whereas cryo-electron microscopy (EM) shows cannabidiol binds to the pocket located between S5 and S6 helices of adjacent subunits of the closed related TRPV2 channel (16Pumroy R.A. Samanta A. Liu Y. Hughes T.E. Zhao S. Yudin Y. Rohacs T. Han S. Moiseenkova-Bell V.Y. Molecular mechanism of TRPV2 channel modulation by cannabidiol.Elife. 2019; 8e48792Crossref PubMed Google Scholar). In this study, we used a combination of patch-clamp recording, site-directed mutagenesis, and molecular docking to reveal that the endogenous TRPV1 agonists AEA, NADA, OEA, and OLDA can bind to the capsaicin-binding pocket near S4 in distinct binding configurations as compared with that of capsaicin. We transiently transfected and expressed mouse TRPV1 in HEK293 cells for patch-clamp recordings, as such an expression system of TRPV1 has been extensively used in our previous studies of TRPV1 channel gating mechanisms (13Yang F. Xiao X. Cheng W. Yang W. Yu P. Song Z. Yarov-Yarovoy V. Zheng J. Structural mechanism underlying capsaicin binding and activation of the TRPV1 ion channel.Nat. Chem. Biol. 2015; 11: 518-524Crossref PubMed Scopus (168) Google Scholar, 14Yang F. Xiao X. Lee B.H. Vu S. Yang W. Yarov-Yarovoy V. Zheng J. The conformational wave in capsaicin activation of transient receptor potential vanilloid 1 ion channel.Nat. Commun. 2018; 9: 2879Crossref PubMed Scopus (32) Google Scholar, 17Yang F. Xu L. Lee B.H. Xiao X. Yarov-Yarovoy V. Zheng J. An unorthodox mechanism underlying voltage sensitivity of TRPV1 ion channel.Adv. Sci. (Weinh.). 2020; 7: 2000575PubMed Google Scholar). Moreover, the sequence identity between mouse and TRPV1 in the is (Fig. We TRPV1 activation in to the endocannabinoids NADA, OEA, and patch-clamp We that all these ligands activated the TRPV1 channel in a (Fig. 1, and NADA, OEA, and OLDA similar for NADA, OEA, and to that of capsaicin whereas AEA a (Fig. to that of We employed as an to activate TRPV1 not bind to the to open the channel. previous has shown that in with capsaicin, such as and not activation (13Yang F. Xiao X. Cheng W. Yang W. Yu P. Song Z. Yarov-Yarovoy V. Zheng J. Structural mechanism underlying capsaicin binding and activation of the TRPV1 ion channel.Nat. Chem. Biol. 2015; 11: 518-524Crossref PubMed Scopus (168) Google Scholar). Moreover, in the related structures that binds to the Structure and gating mechanism of the transient receptor potential channel Mol. Biol. 2018; PubMed Scopus Google Scholar). Therefore, serves as an agonist that the open of endogenous agonists can be from the membrane by to We activation of TRPV1 by of capsaicin and similar open as we (13Yang F. Xiao X. Cheng W. Yang W. Yu P. Song Z. Yarov-Yarovoy V. Zheng J. Structural mechanism underlying capsaicin binding and activation of the TRPV1 ion channel.Nat. Chem. Biol. 2015; 11: 518-524Crossref PubMed Scopus (168) Google (Fig. in activated by endocannabinoids that of activation (Fig. the open of TRPV1 activated by is to and the endocannabinoids a these that the endocannabinoids open TRPV1 that they are agonists for investigate the ligand gating mechanisms of these we these ligands bind to the pocket in TRPV1 as capsaicin. is well that the TRPV1 capsaicin activation of TRPV1 (13Yang F. Xiao X. Cheng W. Yang W. Yu P. Song Z. Yarov-Yarovoy V. Zheng J. Structural mechanism underlying capsaicin binding and activation of the TRPV1 ion channel.Nat. Chem. Biol. 2015; 11: 518-524Crossref PubMed Scopus (168) Google Scholar, Julius D. Molecular for sensitivity to 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). The structures of TRPV1 reveal that the side chain of Y512 serves as a for the in the M. Cao E. Julius D. Cheng Y. Structure of the TRPV1 ion channel determined by electron cryo-microscopy.Nature. 2013; 504: 107-112Crossref PubMed Scopus (1049) Google that the is open to the capsaicin; capsaicin binding this side chain E. Liao M. Cheng Y. Julius D. TRPV1 structures in distinct conformations reveal activation mechanisms.Nature. 2013; 504: 113-118Crossref PubMed Scopus (656) Google which the capsaicin the (13Yang F. Xiao X. Cheng W. Yang W. Yu P. Song Z. Yarov-Yarovoy V. Zheng J. Structural mechanism underlying capsaicin binding and activation of the TRPV1 ion channel.Nat. Chem. Biol. 2015; 11: 518-524Crossref PubMed Scopus (168) Google (Fig. Therefore, the side chain is in is open that the ligand bind We similar to capsaicin, of these endocannabinoids activated the at their for the channel (Fig. whereas largely activated the In residue to the not capsaicin activation (13Yang F. Xiao X. Cheng W. Yang W. Yu P. Song Z. Yarov-Yarovoy V. Zheng J. Structural mechanism underlying capsaicin binding and activation of the TRPV1 ion channel.Nat. Chem. Biol. 2015; 11: 518-524Crossref PubMed Scopus (168) Google Scholar). We also found that can be activated by the endocannabinoids (Fig. these similar voltage as the channel further the of on channel we the activation of channels by and a similar (Fig. the expression of not Therefore, our suggest that AEA, NADA, OEA, and OLDA also bind to the like capsaicin to activate the TRPV1 channel. As the endocannabinoids bind to the we how they bind the previous studies that the binding of capsaicin is by with on the S4 and on the S4-S5 linker (13Yang F. Xiao X. Cheng W. Yang W. Yu P. Song Z. Yarov-Yarovoy V. Zheng J. Structural mechanism underlying capsaicin binding and activation of the TRPV1 ion channel.Nat. Chem. Biol. 2015; 11: 518-524Crossref PubMed Scopus (168) Google Scholar, 14Yang F. Xiao X. Lee B.H. Vu S. Yang W. Yarov-Yarovoy V. Zheng J. The conformational wave in capsaicin activation of transient receptor potential vanilloid 1 ion channel.Nat. Commun. 2018; 9: 2879Crossref PubMed Scopus (32) Google (Fig. in we these two between the endocannabinoids and TRPV1 that these ligands the in their chemical structures (Fig. our by the potential with the capsaicin activation of the largely to the by (Fig. AEA and activated the with similar for AEA and OEA, (Fig. to of the channel (Fig. and that formed between AEA, OEA, and residue NADA and their for for NADA and but the of is that of capsaicin potential with the capsaicin can activate this with a (Fig. AEA, OEA, and OLDA the channel (Fig. and Therefore, on such we that the network between the endocannabinoids and TRPV1 channel is distinct to that of capsaicin, these ligands bind to the with similarities in their chemical investigate binding of the we the with patch-clamp we have employed this to reveal the binding of capsaicin to TRPV1 channel (13Yang F. Xiao X. Cheng W. Yang W. Yu P. Song Z. Yarov-Yarovoy V. Zheng J. Structural mechanism underlying capsaicin binding and activation of the TRPV1 ion channel.Nat. Chem. Biol. 2015; 11: 518-524Crossref PubMed Scopus (168) Google and to channel L. Han Y. X. A. Zheng W. X. Zhao Z. C. P. Yang W. Yang S. Yang F. Molecular mechanisms underlying binding and activation of ion channel.Nat. Commun. 2020; 11: PubMed Scopus Google Scholar). In a chemical of the ligand with a residue on TRPV1, either this or the residue on channel effects on binding studies including our have shown the energy is at (13Yang F. Xiao X. Cheng W. Yang W. Yu P. Song Z. Yarov-Yarovoy V. Zheng J. Structural mechanism underlying capsaicin binding and activation of the TRPV1 ion channel.Nat. Chem. Biol. 2015; 11: 518-524Crossref PubMed Scopus (168) Google Scholar, of the channel by Full Text Full Text PDF PubMed Scopus Google Scholar, G. The of to structural in the of the Full Text PDF PubMed Scopus Google Scholar), a interaction of the two can be the chemical structures of AEA and NADA, we that these two have and but their by (Fig. Therefore, we of such similarities in chemical and with AEA and NADA to investigate how the of endocannabinoids with TRPV1 channel. As we in previous and AEA a as compared with NADA for the channels for AEA and NADA, that the to ligand further the effects of in we employed a (Fig. that the binding of capsaicin to TRPV1 and to (13Yang F. Xiao X. Cheng W. Yang W. Yu P. Song Z. Yarov-Yarovoy V. Zheng J. Structural mechanism underlying capsaicin binding and activation of the TRPV1 ion channel.Nat. Chem. Biol. 2015; 11: 518-524Crossref PubMed Scopus (168) Google Scholar, L. Han Y. X. A. Zheng W. X. Zhao Z. C. P. Yang W. Yang S. Yang F. Molecular mechanisms underlying binding and activation of ion channel.Nat. Commun. 2020; 11: PubMed Scopus Google Scholar), the ligand binding by and the conformational to channel by are As the endocannabinoids are agonists for TRPV1 with a (Fig. we can and and from and and as (13Yang F. Xiao X. Cheng W. Yang W. Yu P. Song Z. Yarov-Yarovoy V. Zheng J. Structural mechanism underlying capsaicin binding and activation of the TRPV1 ion channel.Nat. Chem. Biol. 2015; 11: 518-524Crossref PubMed Scopus (168) Google Scholar, L. Han Y. X. A. Zheng W. X. Zhao Z. C. P. Yang W. Yang S. Yang F. Molecular mechanisms underlying binding and activation of ion channel.Nat. Commun. 2020; 11: PubMed Scopus Google Scholar). the of NADA of AEA (Fig. and We and for a of TRPV1 and the energy (Fig. We that only at residue Y512 the energy the (Fig. in that the of AEA and NADA As we have with many (Fig. with such as and we to potential binding configurations of the endocannabinoids molecular docking in the A. M. J. W. S. A. F. An for the simulation and of PubMed Scopus Google Scholar). we have employed such molecular docking to reveal the binding configuration of chemicals (13Yang F. Xiao X. Cheng W. Yang W. Yu P. Song Z. Yarov-Yarovoy V. Zheng J. Structural mechanism underlying capsaicin binding and activation of the TRPV1 ion channel.Nat. Chem. Biol. 2015; 11: 518-524Crossref PubMed Scopus (168) Google Scholar, Y. Y. Vu S. Yang F. Yarov-Yarovoy V. Y. Zheng J. A distinct structural mechanism TRPV1 activation by Commun. 2019; PubMed Scopus Google Scholar, F. Vu S. Yarov-Yarovoy V. Zheng J. and of a TRPV2 ion Sci. S. A. 2016; PubMed Scopus Google Scholar, Y. Y. Vu S. Yang F. Yarov-Yarovoy V. Y. Zheng J. Structural mechanisms underlying activation of TRPV1 channels by pungent compounds in J. Pharmacol. 2019; Google and S. Yang F. Lee B.H. L. Zheng J. A activation mechanism PubMed Scopus Google Scholar, S. Yang F. J. L. M. Yarov-Yarovoy V. Zheng J. A targets the heat activation of nociceptor Commun. 2015; PubMed Scopus Google Scholar, A. A. Z. Vu S. Y. Zheng J. Yang S. Yang F. A of nociceptor TRPV1 ion 2020; PubMed Scopus Google to the TRPV1 channel. We AEA, NADA, OEA, and OLDA to the (Fig. in We compared the docking that are with our patch-clamp (Fig. and with our previous capsaicin binding (13Yang F. Xiao X. Cheng W. Yang W. Yu P. Song Z. Yarov-Yarovoy V. Zheng J. Structural mechanism underlying capsaicin binding and activation of the TRPV1 ion channel.Nat. Chem. Biol. 2015; 11: 518-524Crossref PubMed Scopus (168) Google (Fig. in and We that these endocannabinoids and capsaicin bind to the they the “tail-up, head-down” binding configuration as capsaicin (Fig. However, the in their binding are AEA, the hydroxyl in formed a with residue which is with our that largely AEA activation and In the between the of capsaicin and residue docking that there between AEA and residue which by the that not largely the AEA activation (Fig. and OEA, a similar binding configuration as AEA (Fig. NADA, in the from the side chain of residue Y512 (Fig. which is with the by our (Fig. a binding configuration, the (Fig. Therefore, our molecular docking in combination with patch-clamp that the endocannabinoids we bind to the with the configuration like capsaicin, but how the endocannabinoids with TRPV1 the to activate TRPV1 is distinct from that of capsaicin. In this we patch-clamp and molecular docking to investigate the activation mechanisms of the endocannabinoids. We found that the endocannabinoids also bind to the of TRPV1, but the in are from of capsaicin. the between capsaicin and is important for binding (13Yang F. Xiao X. Cheng W. Yang W. Yu P. Song Z. Yarov-Yarovoy V. Zheng J. Structural mechanism underlying capsaicin binding and activation of the TRPV1 ion channel.Nat. Chem. Biol. 2015; 11: 518-524Crossref PubMed Scopus (168) Google Scholar), whereas we for endocannabinoids like AEA, similar of ligand that there is As the of the endocannabinoids is that of capsaicin (Fig. 1, A and and the largely to ligand binding (13Yang F. Xiao X. Cheng W. Yang W. Yu P. Song Z. Yarov-Yarovoy V. Zheng J. Structural mechanism underlying capsaicin binding and activation of the TRPV1 ion channel.Nat. Chem. Biol. 2015; 11: 518-524Crossref PubMed Scopus (168) Google Scholar), we the between the and channel is to be as compared with that of capsaicin, which further the binding configuration of endocannabinoids. Moreover, we that the of capsaicin or activation to (Fig. (13Yang F. Xiao X. Cheng W. Yang W. Yu P. Song Z. Yarov-Yarovoy V. Zheng J. Structural mechanism underlying capsaicin binding and activation of the TRPV1 ion channel.Nat. Chem. Biol. 2015; 11: 518-524Crossref PubMed Scopus (168) Google Scholar), whereas of TRPV1 activated by endocannabinoids that of (Fig. 1, and These suggest as the binding configuration of endocannabinoids is as by their the of endocannabinoids to the open of TRPV1 is that of capsaicin or between the endocannabinoids and TRPV1 channel have in the the TRPV1 channel has been pursued as a target for to critical in temperature sensation in of this channel to and in heat which in clinical N.R. Setbacks in the clinical development of TRPV1 antagonists.Open Drug Discov. J. 2009; 1: 1-35Crossref Google Scholar). to TRPV1 such as the have been for effects D. M.J. modulation of TRPV1 as a 2012; PubMed Scopus Google Scholar). the have been widely used as for their effects on the ionotropic cannabinoid receptors such as TRPV1 have to be recognized (8Di Marzo V. Blumberg P.M. Szallasi A. Endovanilloid signaling in pain.Curr. Opin. Neurobiol. 2002; 12: 372-379Crossref PubMed Scopus (239) Google Scholar, 9Akopian A.N. Ruparel N.B. Jeske N.A. Patwardhan A. Hargreaves K.M. Role of ionotropic cannabinoid receptors in peripheral antinociception and antihyperalgesia.Trends Pharmacol. Sci. 2009; 30: 79-84Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar). Therefore, as endocannabinoids and capsaicin bind to the pocket to activate TRPV1, we that identified for capsaicin such as C. M.A. S. M.J. modulation of TRPV1 activation by and acidic Pharmacol. 2012; PubMed Scopus Google and E. X. The of TRPV1 bind ligands and channel Full Text Full Text PDF PubMed Scopus Google Scholar), also channel activation by endocannabinoids. and previous studies have demonstrated the of the in ligand gating of many TRP channels. classic TRPV1 agonists capsaicin and all bind to the pocket (10Gao Y. Cao E. Julius D. Cheng Y. TRPV1 structures in nanodiscs reveal mechanisms of ligand and lipid action.Nature. 2016; 534: 347-351Crossref PubMed Scopus (464) Google Scholar, 12Cao E. Liao M. Cheng Y. Julius D. TRPV1 structures in distinct conformations reveal activation mechanisms.Nature. 2013; 504: 113-118Crossref PubMed Scopus (656) Google Scholar, F. Xiao X. Cheng W. Yang W. Yu P. Song Z. Yarov-Yarovoy V. Zheng J. Structural mechanism underlying capsaicin binding and activation of the TRPV1 ion channel.Nat. Chem. Biol. 2015; 11: 518-524Crossref PubMed Scopus (168) Google Scholar). In to the also bind to this pocket to with the agonists (10Gao Y. Cao E. Julius D. Cheng Y. TRPV1 structures in nanodiscs reveal mechanisms of ligand and lipid action.Nature. 2016; 534: 347-351Crossref PubMed Scopus (464) Google Scholar). Although the pocket in the TRPV2 channel is in L. M.A. Liu Z. Lee microscopy of the TRPV2 ion channel.Nat. Mol. Biol. 2016; PubMed Scopus Google Scholar, J. Samanta A. Moiseenkova-Bell V.Y. Structure of the TRPV2 channel by Commun. 2016; 7: PubMed Scopus Google Scholar), by only critical this pocket we and have vanilloid the TRPV2 channel F. Vu S. Yarov-Yarovoy V. Zheng J. and of a TRPV2 ion Sci. S. A. 2016; PubMed Scopus Google Scholar, F. A. D. C. Blumberg P.M. S. the TRPV2 2016; PubMed Scopus Google Scholar). vanilloid can be by in this pocket of channel F. A. for activation of 2019; PubMed Scopus Google Scholar). channel also binds to this pocket A. J. A. S. Samanta A. Han X. S. M. Rohacs T. Han S. Moiseenkova-Bell V.Y. Structural of channel inhibition by by Mol. Biol. 2018; PubMed Scopus Google Scholar). Therefore, the in TRPV1 and the pocket in TRP channels is a for ligand gating in TRP channels, such a pocket may as a target for development in TRPV1 a from X. of at used in this study, and all of the of on this channel. In to to the of the which not the function of made by and by used to are in from from from and from The of these compounds above from cells in with and for to at the to cells transiently transfected with by the 1 to after of the endocannabinoids compounds the the molecular A. M. J. W. S. A. F. An for the simulation and of PubMed Scopus Google Scholar), in an in G. J. ligand docking with Mol. Biol. 2012; PubMed Scopus Google Scholar). The in a membrane P. J. D. high-resolution and of transmembrane Sci. S. A. PubMed Scopus Google Scholar, V. T. D. Structural for gating in the voltage of a Sci. S. A. 2012; PubMed Scopus Google Scholar, V. D. conformations in the open and closed in structural of Sci. S. A. PubMed Scopus Google Scholar, V. J. D. membrane PubMed Scopus Google Scholar). compounds at the of the binding pocket the S3, and S6 and a to A of for A. with from the data and the of Chem. 2012; PubMed Scopus Google Scholar, with and structures from the and Structural Chem. PubMed Scopus Google Scholar). A of for the they for The energy further for binding energy between the and the channel. The identified as molecular by Meng T.E. system for and Chem. PubMed Scopus Google Scholar). patch-clamp with a with in from their from to recording, by A and used in and for in the The membrane potential at and and at an the membrane potential at for and to voltage from to with a for which to for at the the of voltage to the at and at at temperature with the of 1 such as AEA to membrane by a system The and the ligand to the of on the with a in of the to data from in at used to activate and all channels. are shown as of data between the two with and the of data between with as with and not determined by to the of of ligand binding or channel gating on the of the gating to the of ligand is the for the to the of AEA and NADA (Fig. be formed in of determined The of determined by the energy by is the and is temperature in data are the This F. Xu L. Lee B.H. Xiao X. Yarov-Yarovoy V. Zheng J. An unorthodox mechanism underlying voltage sensitivity of TRPV1 ion channel.Adv. Sci. (Weinh.). 2020; 7: 2000575PubMed Google Scholar). The that they have of with the of this We are to and our for and of endocannabinoids activation of TRPV1 channel by Xiao in at of Y. X. Y. Y. and X. X. data Y. X. Y. and Y. T. Y. L. and X. C. Y. L. and F. Y. Y. X. and F. Y. Y. X. and F. Y. and X. X. and F. Y. F. Y. This by of and to F. of to F. to X. and of to Y.

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