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(Circulation Research. 2003;93:941.)
© 2003 American Heart Association, Inc.

Molecular Medicine

Pharmacological Activation of Normal and Arrhythmia-Associated Mutant KCNQ1 Potassium Channels

Guiscard Seebohm, Michael Pusch, Jun Chen, Michael C. Sanguinetti

From the Department of Physiology and Eccles Program in Human Molecular Biology and Genetics (G.S., J.C., M.C.S.), University of Utah, Salt Lake City, Utah; Istituto di Biofisica (M.P.), Genoa, Italy. Present address for G.S. is Department of Physiology, University of Tübingen, Germany.

Correspondence to Michael Sanguinetti, PhD, Department of Physiology, Eccles Institute of Human Genetics, University of Utah, 15 North 2030 East, Room 4220, Salt Lake City, UT 84112. E-mail michael.sanguinetti{at}hmbg.utah.edu

KCNQ1 -subunits coassemble with KCNE1 ß-subunits to form channels that conduct the slow delayed rectifier K⁺ current (I_Ks) important for repolarization of the cardiac action potential. Mutations in KCNQ1 reduce I_Ks and cause long-QT syndrome, a disorder of ventricular repolarization that predisposes affected individuals to arrhythmia and sudden death. Current therapy for long-QT syndrome is inadequate. R-L3 is a benzodiazepine that activates I_Ks and has the potential to provide gene-specific therapy. In the present study, we characterize the molecular determinants of R-L3 interaction with KCNQ1 channels, use computer modeling to propose a mechanism for drug-induced changes in channel gating, and determine its effect on several long-QT syndrome–associated mutant KCNQ1 channels heterologously expressed in Xenopus oocytes. Scanning mutagenesis combined with voltage-clamp analysis indicated that R-L3 interacts with specific residues located in the 5th and 6th transmembrane domains of KCNQ1 subunits. Most KCNQ1 mutant channels responded to R-L3 similarly to wild-type channels, but one mutant channel (G306R) was insensitive to R-L3 possibly because it disrupted a key component of the drug-binding site.

Key Words: antiarrhythmic drugs • ion channel • arrhythmia

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