{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T17:21:54Z","timestamp":1790443314237,"version":"4.1.0"},"reference-count":53,"publisher":"eLife Sciences Publications, Ltd","license":[{"start":{"date-parts":[[2016,2,12]],"date-time":"2016-02-12T00:00:00Z","timestamp":1455235200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"},{"start":{"date-parts":[[2016,2,12]],"date-time":"2016-02-12T00:00:00Z","timestamp":1455235200000},"content-version":"am","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"},{"start":{"date-parts":[[2016,2,12]],"date-time":"2016-02-12T00:00:00Z","timestamp":1455235200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"funder":[{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["NS002945"],"award-info":[{"award-number":["NS002945"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:p>TRPV1 channels in sensory neurons are integrators of painful stimuli and heat, yet how they integrate diverse stimuli and sense temperature remains elusive. Here, we show that external sodium ions stabilize the TRPV1 channel in a closed state, such that removing the external ion leads to channel activation. In studying the underlying mechanism, we find that the temperature sensors in TRPV1 activate in two steps to favor opening, and that the binding of sodium to an extracellular site exerts allosteric control over temperature-sensor activation and opening of the pore. The binding of a tarantula toxin to the external pore also exerts control over temperature-sensor activation, whereas binding of vanilloids influences temperature-sensitivity by largely affecting the open\/closed equilibrium. Our results reveal a fundamental role of the external pore in the allosteric control of TRPV1 channel gating and provide essential constraints for understanding how these channels can be tuned by diverse stimuli.<\/jats:p>","DOI":"10.7554\/elife.13356","type":"journal-article","created":{"date-parts":[[2016,2,11]],"date-time":"2016-02-11T23:26:07Z","timestamp":1455233167000},"source":"Crossref","is-referenced-by-count":67,"title":["An external sodium ion binding site controls allosteric gating in TRPV1 channels"],"prefix":"10.7554","volume":"5","author":[{"given":"Andres","family":"Jara-Oseguera","sequence":"first","affiliation":[{"name":"Molecular Physiology and Biophysics Section, Porter Neuroscience Research Center, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chanhyung","family":"Bae","sequence":"additional","affiliation":[{"name":"Molecular Physiology and Biophysics Section, Porter Neuroscience Research Center, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3419-0765","authenticated-orcid":true,"given":"Kenton J","family":"Swartz","sequence":"additional","affiliation":[{"name":"Molecular Physiology and Biophysics Section, Porter Neuroscience Research Center, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"4374","published-online":{"date-parts":[[2016,2,12]]},"reference":[{"key":"bib1","doi-asserted-by":"publisher","first-page":"337","DOI":"10.1016\/0024-3205(94)00643-1","article-title":"[3H]Resiniferatoxin binding to pig dorsal horn membranes displays positive cooperativity","volume":"55","author":"Acs","year":"1994","journal-title":"Life Sciences"},{"key":"bib2","doi-asserted-by":"publisher","first-page":"327","DOI":"10.1152\/advan.00006.2002","article-title":"Counting channels: a tutorial guide on ion channel fluctuation analysis","volume":"26","author":"Alvarez","year":"2002","journal-title":"Advances in Physiology Education"},{"key":"bib3","doi-asserted-by":"publisher","first-page":"e51516","DOI":"10.1371\/journal.pone.0051516","article-title":"High yield production and refolding of the double-knot toxin, an activator of TRPV1 channels","volume":"7","author":"Bae","year":"2012","journal-title":"PLoS ONE"},{"key":"bib4","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.11273","article-title":"Structural insights into the mechanism of activation of the TRPV1 channel by a membrane-bound tarantula toxin","volume":"5:e11273","author":"Bae","year":"2016","journal-title":"eLife"},{"key":"bib5","doi-asserted-by":"publisher","first-page":"834","DOI":"10.1016\/j.cell.2010.03.052","article-title":"A bivalent tarantula toxin activates the capsaicin receptor, TRPV1, by targeting the outer pore domain","volume":"141","author":"Bohlen","year":"2010","journal-title":"Cell"},{"key":"bib6","doi-asserted-by":"publisher","first-page":"15494","DOI":"10.1073\/pnas.0406773101","article-title":"Clues to understanding cold sensation: thermodynamics and electrophysiological analysis of the cold receptor TRPM8","volume":"101","author":"Brauchi","year":"2004","journal-title":"Proceedings of the National Academy of Sciences of the United States of America"},{"key":"bib7","doi-asserted-by":"publisher","first-page":"667","DOI":"10.1016\/j.neuron.2012.12.016","article-title":"TRPV1 channels are intrinsically heat sensitive and negatively regulated by phosphoinositide lipids","volume":"77","author":"Cao","year":"2013","journal-title":"Neuron"},{"key":"bib8","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1038\/nature12823","article-title":"TRPV1 structures in distinct conformations reveal activation mechanisms","volume":"504","author":"Cao","year":"2013","journal-title":"Nature"},{"key":"bib9","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1085\/jgp.201311025","article-title":"Divalent cations potentiate TRPV1 channel by lowering the heat activation threshold","volume":"143","author":"Cao","year":"2014","journal-title":"The Journal of General Physiology"},{"key":"bib10","doi-asserted-by":"publisher","first-page":"487","DOI":"10.1146\/annurev.neuro.24.1.487","article-title":"The vanilloid receptor: a molecular gateway to the pain pathway","volume":"24","author":"Caterina","year":"2001","journal-title":"Annual Review of Neuroscience"},{"key":"bib11","doi-asserted-by":"publisher","first-page":"1148","DOI":"10.1016\/j.cell.2014.07.026","article-title":"A molecular framework for temperature-dependent gating of ion channels","volume":"158","author":"Chowdhury","year":"2014","journal-title":"Cell"},{"key":"bib12","doi-asserted-by":"publisher","first-page":"19492","DOI":"10.1073\/pnas.1117485108","article-title":"A thermodynamic framework for understanding temperature sensing by transient receptor potential (tRP) channels","volume":"108","author":"Clapham","year":"2011","journal-title":"Proceedings of the National Academy of Sciences of the United States of America"},{"key":"bib13","doi-asserted-by":"publisher","first-page":"273","DOI":"10.1085\/jgp.201110724","article-title":"Selective disruption of high sensitivity heat activation but not capsaicin activation of TRPV1 channels by pore turret mutations","volume":"139","author":"Cui","year":"2012","journal-title":"The Journal of General Physiology"},{"key":"bib14","doi-asserted-by":"publisher","first-page":"649","DOI":"10.1016\/S0896-6273(01)00487-1","article-title":"Tight steric closure at the intracellular activation gate of a voltage-gated k+ channel","volume":"32","author":"del Camino","year":"2001","journal-title":"Neuron"},{"key":"bib15","doi-asserted-by":"publisher","first-page":"336","DOI":"10.1038\/nature15249","article-title":"Gating machinery of InsP3R channels revealed by electron cryomicroscopy","volume":"527","author":"Fan","year":"2015","journal-title":"Nature"},{"key":"bib16","doi-asserted-by":"publisher","first-page":"708","DOI":"10.1038\/nn.2552","article-title":"Temperature-induced opening of TRPV1 ion channel is stabilized by the pore domain","volume":"13","author":"Grandl","year":"2010","journal-title":"Nature Neuroscience"},{"key":"bib17","doi-asserted-by":"publisher","first-page":"361","DOI":"10.1085\/jgp.201311070","article-title":"Mutation of I696 and W697 in the TRP box of vanilloid receptor subtype i modulates allosteric channel activation","volume":"143","author":"Gregorio-Teruel","year":"2014","journal-title":"The Journal of General Physiology"},{"key":"bib18","doi-asserted-by":"publisher","first-page":"529","DOI":"10.1016\/j.bpj.2015.06.039","article-title":"The integrity of the TRP domain is pivotal for correct TRPV1 channel gating","volume":"109","author":"Gregorio-Teruel","year":"2015","journal-title":"Biophysical Journal"},{"key":"bib19","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1016\/0076-6879(92)07009-D","article-title":"Nonstationary noise analysis and application to patch clamp recordings","volume":"207","author":"Heinemann","year":"1992","journal-title":"Methods Enzymol"},{"key":"bib20","doi-asserted-by":"publisher","first-page":"991","DOI":"10.1007\/978-3-319-05161-1_11","article-title":"High-resolution views of TRPV1 and their implications for the TRP channel superfamily","volume":"223","author":"Hellmich","year":"2014","journal-title":"Handb Exp Pharmacol"},{"key":"bib21","volume-title":"Ion Channels of Excitable Membranes","author":"Hille","year":"2001"},{"key":"bib22","doi-asserted-by":"publisher","first-page":"2401","DOI":"10.1021\/acs.biochem.5b00071","article-title":"Understanding thermosensitive transient receptor potential channels as versatile polymodal cellular sensors","volume":"54","author":"Hilton","year":"2015","journal-title":"Biochemistry"},{"key":"bib23","doi-asserted-by":"publisher","first-page":"2957","DOI":"10.1016\/S0006-3495(03)70022-8","article-title":"Capsaicin activation of the pain receptor, VR1: multiple open states from both partial and full binding","volume":"84","author":"Hui","year":"2003","journal-title":"Biophysical Journal"},{"key":"bib24","doi-asserted-by":"publisher","first-page":"8134","DOI":"10.1073\/pnas.100129497","article-title":"Acid potentiation of the capsaicin receptor determined by a key extracellular site","volume":"97","author":"Jordt","year":"2000","journal-title":"Proceedings of the National Academy of Sciences of the United States of America"},{"key":"bib25","doi-asserted-by":"publisher","first-page":"421","DOI":"10.1016\/S0092-8674(02)00637-2","article-title":"Molecular basis for species-specific sensitivity to \u201chot\u201d chili peppers","volume":"108","author":"Jordt","year":"2002","journal-title":"Cell"},{"key":"bib26","doi-asserted-by":"publisher","first-page":"35690","DOI":"10.1074\/jbc.M113.513374","article-title":"Carboxyl-terminal domain of transient receptor potential vanilloid 1 contains distinct segments differentially involved in capsaicin- and heat-induced desensitization","volume":"288","author":"Joseph","year":"2013","journal-title":"Journal of Biological Chemistry"},{"key":"bib27","doi-asserted-by":"publisher","first-page":"191","DOI":"10.1113\/jphysiol.2005.089888","article-title":"Characterization of a proton-activated, outwardly rectifying anion channel","volume":"567","author":"Lambert","year":"2005","journal-title":"The Journal of Physiology"},{"key":"bib28","doi-asserted-by":"publisher","first-page":"427","DOI":"10.1016\/j.ceca.2007.04.004","article-title":"ThermoTRP channels as modular proteins with allosteric gating","volume":"42","author":"Latorre","year":"2007","journal-title":"Cell Calcium"},{"key":"bib29","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1085\/jgp.201511386","article-title":"Proton block of proton-activated TRPV1 current","volume":"146","author":"Lee","year":"2015","journal-title":"The Journal of General Physiology"},{"key":"bib30","doi-asserted-by":"publisher","first-page":"2112","DOI":"10.1007\/978-1-4614-1533-6_242","volume-title":"Encyclopedia of Metalloproteins","author":"Lev","year":"2013"},{"key":"bib31","doi-asserted-by":"publisher","first-page":"1577","DOI":"10.1038\/nn.4120","article-title":"Physical basis of apparent pore dilation of ATP-activated P2X receptor channels","volume":"18","author":"Li","year":"2015","journal-title":"Nature Neuroscience"},{"key":"bib32","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1038\/nature12822","article-title":"Structure of the TRPV1 ion channel determined by electron cryo-microscopy","volume":"504","author":"Liao","year":"2013","journal-title":"Nature"},{"key":"bib33","doi-asserted-by":"publisher","first-page":"175","DOI":"10.1016\/S0896-6273(00)80357-8","article-title":"Gated access to the pore of a voltage-dependent k+ channel","volume":"19","author":"Liu","year":"1997","journal-title":"Neuron"},{"key":"bib34","doi-asserted-by":"publisher","first-page":"2988","DOI":"10.1016\/S0006-3495(03)74719-5","article-title":"Thermodynamics of heat activation of single capsaicin ion channels VR1","volume":"85","author":"Liu","year":"2003","journal-title":"Biophysical Journal"},{"key":"bib35","doi-asserted-by":"publisher","first-page":"376","DOI":"10.1038\/nature06265","article-title":"Atomic structure of a voltage-dependent k+ channel in a lipid membrane-like environment","volume":"450","author":"Long","year":"2007","journal-title":"Nature"},{"key":"bib36","doi-asserted-by":"publisher","first-page":"469","DOI":"10.1113\/jphysiol.2007.144287","article-title":"Voltage is a partial activator of rat thermosensitive TRP channels","volume":"585","author":"Matta","year":"2007","journal-title":"The Journal of Physiology"},{"key":"bib37","doi-asserted-by":"publisher","first-page":"362","DOI":"10.1016\/j.neuron.2008.04.012","article-title":"A yeast genetic screen reveals a critical role for the pore helix domain in TRP channel gating","volume":"58","author":"Myers","year":"2008","journal-title":"Neuron"},{"key":"bib38","doi-asserted-by":"publisher","first-page":"9377","DOI":"10.1074\/jbc.M709377200","article-title":"Novel gating and sensitizing mechanism of capsaicin receptor (tRPV1): tonic inhibitory regulation of extracellular sodium through the external protonation sites on TRPV1","volume":"283","author":"Ohta","year":"2008","journal-title":"Journal of Biological Chemistry"},{"key":"bib39","doi-asserted-by":"publisher","first-page":"3901","DOI":"10.1529\/biophysj.106.102400","article-title":"On the mechanism of TBA block of the TRPV1 channel","volume":"92","author":"Oseguera","year":"2007","journal-title":"Biophysical Journal"},{"key":"bib40","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1113\/jphysiol.2002.016352","article-title":"Single-channel properties of native and cloned rat vanilloid receptors","volume":"545","author":"Premkumar","year":"2002","journal-title":"The Journal of Physiology"},{"key":"bib41","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/B978-0-12-800181-3.00002-6","article-title":"Temperature sensing by thermal TRP channels: thermodynamic basis and molecular insights","volume":"74","author":"Feng","year":"2014","journal-title":"Current Topics in Membranes"},{"key":"bib42","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1085\/jgp.200308847","article-title":"Low pH potentiates both capsaicin binding and channel gating of VR1 receptors","volume":"122","author":"Ryu","year":"2003","journal-title":"The Journal of General Physiology"},{"key":"bib43","doi-asserted-by":"publisher","first-page":"12797","DOI":"10.1523\/JNEUROSCI.2324-07.2007","article-title":"Uncoupling proton activation of vanilloid receptor TRPV1","volume":"27","author":"Ryu","year":"2007","journal-title":"Journal of Neuroscience"},{"key":"bib44","doi-asserted-by":"publisher","first-page":"704","DOI":"10.1038\/nsmb.1633","article-title":"Structural determinants of gating in the TRPV1 channel","volume":"16","author":"Salazar","year":"2009","journal-title":"Nature Structural &#38; Molecular Biology"},{"key":"bib45","doi-asserted-by":"publisher","first-page":"787","DOI":"10.1111\/j.1476-5381.2011.01601.x","article-title":"The thermo-TRP ion channel family: properties and therapeutic implications","volume":"165","author":"Vay","year":"2012","journal-title":"British Journal of Pharmacology"},{"key":"bib46","doi-asserted-by":"publisher","first-page":"748","DOI":"10.1038\/nature02732","article-title":"The principle of temperature-dependent gating in cold- and heat-sensitive TRP channels","volume":"430","author":"Voets","year":"2004","journal-title":"Nature"},{"key":"bib47","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1007\/112_2011_5","article-title":"Quantifying and modeling the temperature-dependent gating of TRP channels","volume":"162","author":"Voets","year":"2012","journal-title":"Rev Physiol Biochem Pharmacol"},{"key":"bib48","doi-asserted-by":"publisher","first-page":"50","DOI":"10.1038\/nature14063","article-title":"Structure of the rabbit ryanodine receptor RyR1 at near-atomic resolution","volume":"517","author":"Yan","year":"2015","journal-title":"Nature"},{"key":"bib49","doi-asserted-by":"publisher","first-page":"7083","DOI":"10.1073\/pnas.1000357107","article-title":"Thermosensitive TRP channel pore turret is part of the temperature activation pathway","volume":"107","author":"Yang","year":"2010","journal-title":"Proceedings of the National Academy of Sciences of teh United States of America"},{"key":"bib50","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1085\/jgp.201311024","article-title":"Divalent cations activate TRPV1 through promoting conformational change of the extracellular region","volume":"143","author":"Yang","year":"2014","journal-title":"The Journal of General Physiology"},{"key":"bib51","doi-asserted-by":"publisher","first-page":"e03255","DOI":"10.7554\/eLife.03255","article-title":"High temperature sensitivity is intrinsic to voltage-gated potassium channels","volume":"3","author":"Yang","year":"2014","journal-title":"eLife"},{"key":"bib52","doi-asserted-by":"publisher","first-page":"1743","DOI":"10.1016\/j.bpj.2010.07.022","article-title":"Kinetic and energetic analysis of thermally activated TRPV1 channels","volume":"99","author":"Yao","year":"2010","journal-title":"Biophysical Journal"},{"key":"bib53","doi-asserted-by":"publisher","first-page":"E125","DOI":"10.1073\/pnas.1008272107","article-title":"Pore turret of thermal TRP channels is not essential for temperature sensing","volume":"107","author":"Yao","year":"2010","journal-title":"Proceedings of the National Academy of Sciences of the United States of America"}],"container-title":["eLife"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/cdn.elifesciences.org\/articles\/13356\/elife-13356-v1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/cdn.elifesciences.org\/articles\/13356\/elife-13356-v1.xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/elifesciences.org\/articles\/13356","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,11]],"date-time":"2023-10-11T20:48:52Z","timestamp":1697057332000},"score":1,"resource":{"primary":{"URL":"https:\/\/elifesciences.org\/articles\/13356"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,2,12]]},"references-count":53,"alternative-id":["10.7554\/eLife.13356"],"URL":"https:\/\/doi.org\/10.7554\/elife.13356","archive":["CLOCKSS"],"relation":{"has-review":[{"id-type":"doi","id":"10.7554\/eLife.13356.035","asserted-by":"object"},{"id-type":"doi","id":"10.7554\/eLife.13356.036","asserted-by":"object"}]},"ISSN":["2050-084X"],"issn-type":[{"value":"2050-084X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,2,12]]},"article-number":"e13356"}}