Novel arrhythmogenic mechanism revealed by a Long-QT syndrome mutation in the cardiac Na+ channel

被引:97
作者
Abriel, H
Cabo, C
Wehrens, XHT
Rivolta, I
Motoike, HK
Memmi, M
Napolitano, C
Priori, SG
Kass, RS
机构
[1] Columbia Univ Coll Phys & Surg, Dept Pharmacol, New York, NY 10032 USA
[2] IRCCS, Fdn Salvatore Maugeri, Mol Cardiol Lab, Pavia, Italy
关键词
long-QT syndrome; Na+ channel; genetics; arrhythmias;
D O I
10.1161/hh0701.089668
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Variant 3 of the congenital long-QT syndrome (LQTS-3) is caused by mutations in the gene encoding the alpha subunit of the cardiac Na+ channel. In the present study, we report a novel LQTS-3 mutation, E1295K (EK), and describe its functional consequences when expressed in HEK293 cells. The clinical phenotype of the proband indicated QT interval prolongation in the absence of T-wave morphological abnormalities and a steep QT/R-R relationship, consistent with an LQTS-3 lesion. However, biophysical analysis of mutant channels indicates that the EK mutation changes channel activity in a manner that is distinct from previously investigated LQTS-3 mutations. The EK mutation causes significant positive shifts in the half-maximal voltage (V-1/2) of steady-state inactivation and activation (+5.2 and +3.4 mV, respectively). These gating changes shift the window of voltages over which Na+ channels do not completely inactivate without altering the magnitude of these currents. The change in voltage dependence of window currents suggests that this alteration in the voltage dependence of Na+ channel gating may cause marked changes in action potential duration because of the unique voltage-dependent rectifying properties of cardiac K+ channels that underlie the plateau and terminal repolarization phases of the action potential. Na+ channel window current is likely to have a greater effect on net membrane current at more positive potentials (EK channels) where total K+ channel conductance is low than at more negative potentials (wild-type channels), where total K+ channel conductance is high. These findings suggest a fundamentally distinct mechanism of arrhythmogenesis for congenital LQTS-3.
引用
收藏
页码:740 / 745
页数:6
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