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A Single Residue in the S6 Transmembrane Domain Governs the Differential Flecainide Sensitivity of Voltage-Gated Potassium Channels

Montreal Heart Institute and Department of Medicine (D.H., A.M., Z.W., S.N.), and Departments of Pharmacology (D.H.) and Physiology (M.S., L.P., R.S.), University of Montreal, Montreal, Quebec, Canada; and Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada (S.N.)

Flecainide has been used to differentiate Kv4.2-based transient-outward K⁺-currents (flecainide-sensitive) from Kv1.4-based (flecainide-insensitive). We found that flecainide also inhibits ultrarapid delayed rectifier (I_Kur) currents in Xenopus laevis oocytes carried by Kv3.1 subunits (IC₅₀, 28.3 ± 1.3 µM) more strongly than Kv1.5 currents corresponding to human I_Kur (IC₅₀, 237.1 ± 6.2 µM). The present study examined molecular motifs underlying differential flecainide sensitivity. An initial chimeric approach pointed to a role for S6 and/or carboxyl-terminal sites in Kv3.1/Kv1.5 sensitivity differences. We then looked for homologous amino acid residues of the two sensitive subunits (Kv4.2 and Kv3.1) different from homologous residues for insensitive subunits (Kv1.4 and Kv1.5). Three candidate sites were identified: two in the S5-S6 linker and one in the S6 segment. Mutation of the proximal S5-S6 linker site failed to alter flecainide sensitivity. Mutation at the more distal site in Kv1.5 (V481L) modestly increased sensitivity, but the reciprocal Kv3.1 mutation (L401V) had no effect. S6 mutants caused marked changes: flecainide sensitivity decreased 8-fold for Kv3.1 L422I (IC₅₀, 213 ± 9 µM) and increased 7-fold for Kv1.5 I502L (IC₅₀, 35.6 ± 1.9 µM). Corresponding mutations reversed flecainide sensitivity of Kv1.4 and Kv4.2; L392I decreased Kv4.2 sensitivity by 17-fold (IC₅₀ of 37.4 ± 6.9 to 628 ± 36 µM); I547L increased Kv1.4 sensitivity by 15-fold (IC₅₀ of 706 ± 37 to 40.9 ± 7.3 µM). Our observations indicate that the flecainide sensitivity differences among these four voltage-gated K⁺-channels are determined by whether an isoleucine or a leucine is present at a specific amino acid location.

Received for publication November 22, 2004.

Accepted for publication May 9, 2005.

Address correspondence to: Dr. Stanley Nattel, Research Center, Montreal Heart Institute, 5000 Belanger St E, Montreal, Quebec, Canada, H1T 1C8. E-mail: stanley.nattel{at}icm-mhi.org

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