title: An external sodium ion binding site controls allosteric gating in TRPV1 channels.
abstract: 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.
authors.affiliation: Molecular Physiology and Biophysics Section, Porter Neuroscience Research Center, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, United States.
authors.forename: Andres
authors.initials: A
authors.lastname: Jara-Oseguera
authors.affiliation: Molecular Physiology and Biophysics Section, Porter Neuroscience Research Center, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, United States.
authors.forename: Chanhyung
authors.initials: C
authors.lastname: Bae
authors.affiliation: Molecular Physiology and Biophysics Section, Porter Neuroscience Research Center, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, United States.
authors.forename: Kenton J
authors.identifier: http://orcid.org/0000-0003-3419-0765
authors.initials: KJ
authors.lastname: Swartz
mesh_terms: D000494:Allosteric Regulation; D001547:Benzaldehydes / Q000378:metabolism; D001665:Binding Sites; D007477:Ions / Q000378:metabolism*; D011485:Protein Binding; D012964:Sodium / Q000378:metabolism*; D013111:Spider Venoms / Q000378:metabolism; D050916:TRPV Cation Channels / Q000378:metabolism*
chemical_list: D001547:Benzaldehydes; D007477:Ions; D013111:Spider Venoms; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; D012964:Sodium; C100058:vanillin
keywords: DkTx; biophysics; gating; rat; sodium ion binding site; structural biology; temperature sensing