title: The biophysical and molecular basis of TRPV1 proton gating.
abstract: The capsaicin receptor TRPV1, a member of the transient receptor potential family of non-selective cation channels is a polymodal nociceptor. Noxious thermal stimuli, protons, and the alkaloid irritant capsaicin open the channel. The mechanisms of heat and capsaicin activation have been linked to voltage-dependent gating in TRPV1. However, until now it was unclear whether proton activation or potentiation or both are linked to a similar voltage-dependent mechanism and which molecular determinants underlie the proton gating. Using the whole-cell patch-clamp technique, we show that protons activate and potentiate TRPV1 by shifting the voltage dependence of the activation curves towards more physiological membrane potentials. We further identified a key residue within the pore region of TRPV1, F660, to be critical for voltage-dependent proton activation and potentiation. We conclude that proton activation and potentiation of TRPV1 are both voltage dependent and that amino acid 660 is essential for proton-mediated gating of TRPV1.
authors.affiliation: Department of Pain Biology, Pfizer Global Research and Development, Sandwich Laboratories, Kent, UK.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Aneiros
authors.forename: Lishuang
authors.initials: L
authors.lastname: Cao
authors.forename: Marianthi
authors.initials: M
authors.lastname: Papakosta
authors.forename: Edward B
authors.initials: EB
authors.lastname: Stevens
authors.forename: Stephen
authors.initials: S
authors.lastname: Phillips
authors.forename: Christian
authors.initials: C
authors.lastname: Grimm
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000596:Amino Acids / Q000235:genetics / Q000378:metabolism; D002211:Capsaicin / Q000378:metabolism; D002460:Cell Line; D006358:Hot Temperature; D006801:Humans; D015640:Ion Channel Gating; D008954:Models, Biological; D008958:Models, Molecular; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D020125:Mutation, Missense; D018408:Patch-Clamp Techniques; D011522:Protons; D050916:TRPV Cation Channels / Q000235:genetics / Q000378:metabolism*
chemical_list: D000596:Amino Acids; D050505:Mutant Proteins; D011522:Protons; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; D002211:Capsaicin