肾上腺素诱导性长QT综合征的分子机制

A molecular mechanism for adrenergic-induced long QT syndrome
2014-07-18 15:58发表评论
作者:Wu, J., Naiki, N., Ding, W.-G., Ohno, S., Kato, K., Zang, W.-J., Delisle, B.P., Matsuura, H., Horie, M.
机构: 西安交通大学医学院药理学系
期刊: J AM COLL CARDIOL 2014年3月8期63卷

Abstract
Objectives: This study sought to explore molecular mechanisms underlying the adrenergic-induced QT prolongation associated with KCNQ1 mutations. Background: The most frequent type of congenital long QT syndrome is LQT1, which is caused by mutations in the gene (KCNQ1) that encodes the alpha subunit of the slow component of delayed rectifier K+ current (IKs) channel. We identified 11 patients from 4 unrelated families that are heterozygous for KCNQ1-G269S. Most patients remained asymptomatic, and their resting corrected QT intervals ranged from normal to borderline but were prolonged significantly during exercise. Methods: Wild-type (WT) KCNQ1 and/or KCNQ1-G269S (G269S) were expressed in mammalian cells with KCNE1. I Ks-like currents were measured in control conditions or after isoproterenol or protein kinase A (PKA) stimulation using the patch-clamp technique. Additionally, experiments that incorporated the phosphomimetic KCNQ1 substitution, S27D, in WT or KCNQ1-G269S were also performed. Results: The coexpression of WT-KCNQ1 with varying amounts of G269S decreased IKs, shifted the current-voltage I-V relation of IKs to more positive potentials, and accelerated the IKs deactivation rates in a concentration-dependent manner. In addition, the coexpression of G269S and WT blunted the activation of IKs in response to isoproterenol or PKA stimulation. Lastly, a phosphomimetic substitution in G269S did not show an increased IKs. Conclusions: G269S modestly affected IKs in control conditions, but it almost completely blunted IKs responsiveness in conditions that simulate or mimic PKA phosphorylation of KCNQ1. This insensitivity to PKA stimulation may explain why patients with G269S mutation showed an excessive prolongation of QT intervals on exercise. © 2014 by the American College of Cardiology Foundation Published by Elsevier Inc.

 

通讯机构:Horie, M.; Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Seta-Tsukinowa-cho, Otsu, Shiga 520-2192, Japan
学科代码:心血管病学   关键词:heterologous expression; KCNQ1 ,中国作者重要发表 爱思唯尔医学网, Elseviermed
来源: Scopus
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