Molecular basis for Kv1.5 channel block: conservation of drug binding sites among voltage-gated K+ channels

Kv1.5 channels conduct the ultrarapid delayed rectifier current (IKur) that contributes to action potential repolarization of human atrial myocytes. Block of these channels has been proposed as a treatment for atrial arrhythmias. Here we report a novel and potent inhibitor of Kv1.5 potassium channel...

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Bibliographic Details
Published in:The Journal of biological chemistry 2004-01, Vol.279 (1), p.394
Main Authors: Decher, Niels, Pirard, Bernard, Bundis, Florian, Peukert, Stefan, Baringhaus, Karl-Heinz, Busch, Andreas E, Steinmeyer, Klaus, Sanguinetti, Michael C
Format: Article
Language:English
Subjects:
Amino Acid Substitution
Animals
Binding Sites
Humans
Kv1.5 Potassium Channel
Membrane Potentials - drug effects
Models, Molecular
Mutagenesis, Site-Directed
Oocytes
ortho-Aminobenzoates - pharmacology
Potassium Channel Blockers - pharmacology
Potassium Channels - chemistry
Potassium Channels - drug effects
Potassium Channels - physiology
Potassium Channels, Voltage-Gated - chemistry
Potassium Channels, Voltage-Gated - drug effects
Potassium Channels, Voltage-Gated - genetics
Potassium Channels, Voltage-Gated - physiology
Protein Conformation
Protein Structure, Secondary
Recombinant Proteins - chemistry
Recombinant Proteins - drug effects
Recombinant Proteins - metabolism
Sulfonamides - pharmacology
Xenopus laevis
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Summary:Kv1.5 channels conduct the ultrarapid delayed rectifier current (IKur) that contributes to action potential repolarization of human atrial myocytes. Block of these channels has been proposed as a treatment for atrial arrhythmias. Here we report a novel and potent inhibitor of Kv1.5 potassium channels, N-benzyl-N-pyridin-3-yl-methyl-2-(toluene-4-sulfonylamino)-benzamide hydrochloride (S0100176), which exhibits features consistent with preferential block of the open state. The IC50 of S0100176 for Kv1.5 expressed in Xenopus oocytes was 0.7 microm. Ala-scanning mutagenesis within the pore helix and the S6 segment, regions that form the walls of the central cavity, was combined with voltage clamp analysis to identify point mutations that altered drug affinity. This approach identified Thr-479, Thr-480, Val-505, Ile-508, and Val-512 as the most important residues for block by S0100176. Mutations of these key residues to Ala or other amino acids caused marked changes in the IC50 of S0100176 (p
ISSN:0021-9258
DOI:10.1074/jbc.M307411200