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(Circulation Research. 2000;86:492.)
© 2000 American Heart Association, Inc.

Editorials

LQT2

Amplitude Reduction and Loss of Selectivity in the Tail That Wags the HERG Channel

Gail A. Robertson

From the Department of Physiology and Cardiovascular Research Center, University of Wisconsin – Madison Medical School, Madison, Wis.

Correspondence to Gail Robertson, Department of Physiology, University of Wisconsin – Madison Medical School, 1300 University Ave, Madison, WI 53706. E-mail robertson@physiology.wisc.edu

Key Words: LQT2 • HERG • selectivity • K⁺ channels

	Introduction

 
Without the ion selectivity of voltage-gated ion channels, excitable cells could not generate more than a few millivolts of resting potential, much less produce action potentials. Even when the loss of selectivity occurs in just one type of K⁺ channel in the heart, the outcome may be catastrophic, suggests a report in this issue of Circulation Research.¹ A defect in K⁺ selectivity caused by a mutation near the "signature sequence" in the pore of HERG channel subunits may contribute as a new mechanism to the prolongation of the action potential and the associated susceptibility to life-threatening torsades de pointes arrhythmias.

Since chromosome 7-linked long-QT syndrome (LQT2) was first mapped to HERG,² a relative of the Drosophila and mammalian eag genes,³ we have learned much about the pathology of the disease and the underlying physiological mechanisms that have gone awry. In heterologous expression systems, the subunits encoded by the wild-type HERG gene assemble to form channels with the functional properties of I_Kr,^{4 5} an unusual repolarizing current first identified by its sensitivity to the antiarrhythmic agent E-4031.⁶ Our understanding of how I_Kr participates in repolarization has emerged largely from voltage-clamp analyses of the remarkable tail currents dominating the HERG current profile. At the positive voltages typically reached at the peak or plateau of the ventricular action potential, much of the current is suppressed by a rapid inactivation mechanism.^{4 5 7 8 9 10} As repolarization ensues, HERG channels recover from inactivation and linger in a highly stable open state before closing.¹¹ The result is . . . [Full Text of this Article]

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