Drug-Binding Sites of Cardiac Sodium Channel

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概要

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• Lidocaine and other local anesthetic drugs block voltage-gated Na channels. It is generally accepted that these drugs bind in the inner pore of Na channels and a phenylalanine (Phe) in domain IV, S6 (Phe1760 in Na<SUB>v</SUB>1.5) is critical for drug-induced use-dependent block. We examined the role of another candidate of drug-binding sites, mid-segment domain I and domain III S6 residues (Asn406, Leu1462) in voltage-dependent gating and antiarrhythmic block. Whole-cell Na currents were measured in HEK293 cells transiently expressing the recombinant wild type (WT) or mutant channels, and the beta-1 subunit. N406 mutants (N406A, N406C) and L1462 mutants (L1462A, L1462C, L1462F) shifted the voltage dependence of fast inactivation towards more negative direction, or accelerated the current decay, and increased the component of intermediate inactivation. N406A and L1462E decreased use-dependent block by flecainide with a decreased affinity for activated channels, while L1462F increased flecainide block with an increased affinity for activated channels. Internally applied charged MTSES blocked L1462C at high rates of stimulation (20 Hz). These results suggest that N406 and L1462 face the pore in the open state and interact with antiarrhytnmic drugs. The drug binding to a key residue, F1760 and additional interaction with N406 and L1462 would place the drug to one side of the channel pore, not in contact with domain II, S6, which may stabilize or induce fast and intermediate inactivation.

著者

• Sunami Akihiko

  Department Of Cardiovascular Diseases Mri Tokyo Medical And Dental University

• Sunami Akihiko

  Department of Pharmaceutical Sciences, International University of Health and Welfare

関連論文

• -P13-REASSESSMENT OF THE KINETICS OF USE-DEPENDENT BLOCK OF THE V_ AND THE Na^+ CURRENT BY CLASS 1 AGENTS : Electrophysiology : FREE COMMUNICATIONS(III) : PROCEEDINGS OF THE 53th ANNUAL SCIENTIFIC MEETING OF THE JAPANESE CIRCULATION SOCIETY
• Drug-Binding Sites of Cardiac Sodium Channel

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