A more recent version of this article appeared on July 6, 2001

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(Circulation Research. 2001;0:hh1301.093633.)
© 2001 American Heart Association, Inc.

Article

Molecular Interactions Between Two Long-QT Syndrome Gene Products, HERG and KCNE2, Rationalized by In Vitro and In Silico Analysis

Reza Mazhari, Joseph L. Greenstein, Raimond L. Winslow, Eduardo Marbán H. Bradley Nuss

From the Department of Medicine (R.M., E.M., H.B.N.), Whitaker Biomedical Engineering Institute and Center for Computational Medicine and Biology (J.L.G., R.L.W., E.M.), and Institute of Molecular Cardiobiology (R.M., R.L.W., E.M., H.B.N.), Johns Hopkins University, Baltimore, Md.

Correspondence to H. Bradley Nuss, PhD, Institute of Molecular Cardiobiology, Johns Hopkins School of Medicine, 720 Rutland Ave, Ross Building 844, Baltimore, MD 21205. E-mail bradnuss{at}mail.jhmi.edu

Abstract

Abstract—The cardiac delayed rectifier potassium current mediates repolarization of the action potential and underlies the QT interval of the ECG. Mutations in either of the two molecular components of the rapid delayed rectifier (I_K,r), HERG and KCNE2, have been linked to heritable or acquired long-QT syndrome. Mechanisms whereby mutations of KCNE2 produce fatal cardiac arrhythmias characteristic of long-QT syndrome remain unclear. In this study, we characterize functional interactions between HERG and KCNE2 with a view to defining underlying mechanisms for action potential prolongation and long-QT syndrome. Whereas coexpression of hKCNE2 with HERG alters both kinetics and density of ionic current, incorporation of these effects into a quantitative model of the action potential predicts that only changes in current density significantly affect repolarization. Thus, the primary functional consequence of hKCNE2 on action potential morphology is through modulation of I_K,r density, as predicted by the model. Mutations associated with long-QT syndrome that result only in modest changes of gating kinetics may be epiphenomena or may modulate action potential repolarization via interaction with alternative pore-forming potassium channel subunits.

Key Words: delayed rectifier potassium channels • Markov chains • action potential • arrhythmia • accessory proteins

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