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Cardiovascular Research 2003 57(3):642-650; doi:10.1016/S0008-6363(02)00778-2
© 2003 by European Society of Cardiology
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Copyright © 2003, European Society of Cardiology

[K+]o-dependent change in conformation of the HERG1 long QT mutation N629D channel results in partial reversal of the in vitro disease phenotype

Guo Qi Teng, James P Lees-Miller, Yanjun Duan, Bao-Tsen Li, Pin Li and Henry J Duff*

Department of Medicine, University of Calgary, 3330 Hospital Drive N.W., Calgary, Alberta, Canada T2N 4N1

* Corresponding author. Tel.: +1-403-220-6841; fax: +1-403-270-0313. hduff{at}ucalgary.ca

Objectives: We hypothesized that exposure of N629D/wildtype channels to transient increases in [K+]o could alter the conformation of the outer vestibule and thus reverse the disease phenotype. N629D is a recently described mutation of the HERG1 gene that causes familial long QT syndrome. This mutation alters the pore signature sequence resulting in loss of K+ selectivity. Previous studies have reported that enforced occupancy of [K+]o at sites near the selectivity filter alters the conformation/folding of the outer vestibule of the Kv2.1 channel. Methods: Since the long QT syndrome is manifest in individuals who are heterozygous for this HERG trait, we co-expressed N629D and the wildtype at equimolar concentrations. Results: Co-expression of N629D/wildtype in Xenopus oocytes and mammalian cells resulted in a channel with a positive shift in reversal potential and a loss in the outward tail current, relative to the wildtype. Exposure of the N629D/wildtype to transient increases in [K+]o from 5 to 40 mM/l changed the tail current from inward to outward during repolarization and restored the reversal potential to values similar to the wildtype. These findings in Xenopus oocytes were also seen when N620D/wildtype channels were expressed in mammalian cells. These [K+]o-dependent changes persisted for hours after the [K+]o was returned to 2.5 mM. This potential therapeutic effect began with increases in [K+]o from 2.5 to 5 mM. Conclusions: This study reports a novel therapeutic strategy and mechanism to partially restore physiologic function in this HERG LQTS mutation.

KEYWORDS Arrhythmia (mechanisms); Intra/extracellular ions; Ion channels; K-channel; Long QT syndrome


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