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(Circulation. 2003;107:2233.)
© 2003 American Heart Association, Inc.

Basic Science Reports

Non-Equilibrium Gating in Cardiac Na⁺ Channels

An Original Mechanism of Arrhythmia

Colleen E. Clancy, PhD; Michihiro Tateyama, PhD; Huajun Liu, MD; Xander H.T. Wehrens, MD, PhD; Robert S. Kass, PhD

From the Department of Pharmacology, Columbia University College of Physicians and Surgeons, New York, NY.

Correspondence to Robert S. Kass, PhD, Department of Pharmacology, Columbia University College of Physicians and Surgeons, 630 W 168th St, New York, NY 10032. E-mail rsk20{at}columbia.edu

Background— Many long-QT syndrome (LQTS) mutations in the cardiac Na⁺ channel result in a gain of function due to a fraction of channels that fail to inactivate (burst), leading to sustained current (I_sus) during depolarization. However, some Na⁺ channel mutations that are causally linked to cardiac arrhythmia do not result in an obvious gain of function as measured using standard patch-clamp techniques. An example presented here, the SCN5A LQTS mutant I1768V, does not act to increase I_sus (<0.1% of peak) compared with wild-type (WT) channels. In fact, it is difficult to reconcile the seemingly innocuous kinetic alterations in I1768V as measured during standard protocols under steady-state conditions with the disease phenotype.

Methods and Results— We developed new experimental approaches based on theoretical analyses to investigate Na⁺ channel gating under non-equilibrium conditions, which more closely approximate physiological changes in membrane potential that occur during the course of a cardiac action potential. We used this new approach to investigate channel-gating transitions that occur subsequent to channel activation.

Conclusions— Our data suggest an original mechanism for development of LQT-3 arrhythmias. This work demonstrates that a combination of computational and experimental analysis of mutations provides a framework to understand complex mechanisms underlying a range of disorders, from molecular defect to cellular and systems function.

Key Words: arrhythmia • remodeling • sodium • long-QT syndrome

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