title: Involvement of local anesthetic binding sites on IVS6 of sodium channels in fast and slow inactivation.
abstract: Local anesthetics (LAs) block Na(+) channels with a higher affinity for the fast or slow inactivated state of the channel. Their binding to the channel may stabilize fast inactivation or induce slow inactivation. We examined the role of the LA binding sites on domain IV, S6 (IVS6) of Na(+) channels in fast and slow inactivation by studying the gating properties of the mutants on IVS6 affecting LA binding. Mutation of the putative LA binding site, F1579C, inhibited fast and slow inactivation. Mutations of another putative LA binding site, Y1586C, and IVS6 residue involved in LA access and binding, I1575C, both enhanced fast and slow inactivation. None of the mutations affected channel activation. These results suggest that the LA binding site on IVS6 is involved in slow inactivation as well as fast inactivation, and these two gatings are coupled at the binding site.
authors.affiliation: Department of Clinical Pharmacology, Medical Research Institute, Tokyo Medical and Dental University, Japan.
authors.forename: Chang-Xi
authors.initials: CX
authors.lastname: Bai
authors.forename: Ian W
authors.initials: IW
authors.lastname: Glaaser
authors.forename: Tohru
authors.initials: T
authors.lastname: Sawanobori
authors.forename: Akihiko
authors.initials: A
authors.lastname: Sunami
mesh_terms: D000779:Anesthetics, Local / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D006801:Humans; D015640:Ion Channel Gating; D009154:Mutation; D018408:Patch-Clamp Techniques; D017434:Protein Structure, Tertiary; D021122:Protein Subunits; D051381:Rats; D015222:Sodium Channels / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014162:Transfection
chemical_list: D000779:Anesthetics, Local; D021122:Protein Subunits; D015222:Sodium Channels