title: Common molecular determinants of local anesthetic, antiarrhythmic, and anticonvulsant block of voltage-gated Na+ channels.
abstract: Voltage-gated Na+ channels are the molecular targets of local anesthetics, class I antiarrhythmic drugs, and some anticonvulsants. These chemically diverse drugs inhibit Na+ channels with complex voltage- and frequency-dependent properties that reflect preferential drug binding to open and inactivated channel states. The site-directed mutations F1764A and Y1771A in transmembrane segment IVS6 of type IIA Na+ channel alpha subunits dramatically reduce the affinity of inactivated channels for the local anesthetic etidocaine. In this study, we show that these mutations also greatly reduce the sensitivity of Na+ channels to state-dependent block by the class Ib antiarrhythmic drug lidocaine and the anticonvulsant phenytoin and, to a lesser extent, reduce the sensitivity to block by the class Ia and Ic antiarrhythmic drugs quinidine and flecainide. For lidocaine and phenytoin, which bind preferentially to inactivated Na+ channels, the mutation F1764A reduced the affinity for binding to the inactivated state 24.5-fold and 8.3-fold, respectively, while Y1771A had smaller effects. For quinidine and flecainide, which bind preferentially to the open Na+ channels, the mutations F1764A and Y1771A reduced the affinity for binding to the open state 2- to 3-fold. Thus, F1764 and Y1771 are common molecular determinants of state-dependent binding of diverse drugs including lidocaine, phenytoin, flecainide, and quinidine, suggesting that these drugs interact with a common receptor site. However, the different magnitude of the effects of these mutations on binding of the individual drugs indicates that they interact in an overlapping, but nonidentical, manner with a common receptor site. These results further define the contributions of F1764 and Y1771 to a complex drug receptor site in the pore of Na+ channels.
authors.affiliation: Department of Pharmacology, University of Washington, Scattle 98195-7280, USA.
authors.forename: D S
authors.initials: DS
authors.lastname: Ragsdale
authors.forename: J C
authors.initials: JC
authors.lastname: McPhee
authors.forename: T
authors.initials: T
authors.lastname: Scheuer
authors.forename: W A
authors.initials: WA
authors.lastname: Catterall
mesh_terms: D000779:Anesthetics, Local / Q000494:pharmacology*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D000927:Anticonvulsants / Q000494:pharmacology*; D001665:Binding Sites / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D005424:Flecainide / Q000494:pharmacology; D015640:Ion Channel Gating / Q000187:drug effects*; D008012:Lidocaine / Q000494:pharmacology; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D010672:Phenytoin / Q000494:pharmacology; D011802:Quinidine / Q000494:pharmacology; D051381:Rats; D011994:Recombinant Proteins / Q000187:drug effects; D015222:Sodium Channels / Q000187:drug effects* / Q000235:genetics; D013329:Structure-Activity Relationship
chemical_list: D000779:Anesthetics, Local; D000889:Anti-Arrhythmia Agents; D000927:Anticonvulsants; D011994:Recombinant Proteins; D015222:Sodium Channels; D010672:Phenytoin; D008012:Lidocaine; D011802:Quinidine; D005424:Flecainide