A Molecular Mechanism for Adrenergic-Induced Long QT Syndrome
A Molecular Mechanism for Adrenergic-Induced Long QT Syndrome
复制标题
肾上腺素诱导的长 QT 综合征的分子机制
DOI：
10.1016/j.jacc.2013.08.1648
复制
发表时间：
2014-03-04
影响因子：
24
通讯作者：
Horie, Minoru
中科院分区：
文献类型：
--
作者：
Wu, Jie;Naiki, Nobu;Horie, Minoru
目的探讨KCNQ 1基因突变引起的肾上腺素能性QT间期延长的分子机制。背景LQT 1是最常见的先天性长QT综合征类型，它是由编码延迟整流钾电流（I-Ks）慢成分α亚基的基因（KCNQ 1）突变引起的。我们从4个不相关的KCNQ 1-G269 S杂合子家族中确定了11例患者。大多数患者仍无症状，他们的静息校正QT间期范围从正常到边界，但延长显着exercise.Methods野生型（WT）KCNQ 1和/或KCNQ 1-G269 S（G269 S）在哺乳动物细胞中表达KCNE 1。在对照条件下或异丙肾上腺素或蛋白激酶A（PKA）刺激后，使用膜片钳技术测量I-Ks样电流。结果WT-KCNQ 1与不同量的G269 S共表达可降低IKs，使IKs的电流-电压I-V关系向更正的电位移动，并以浓度依赖性方式加速IKs的失活速率。此外，G269 S和WT的共表达减弱了IKs对异丙肾上腺素或PKA刺激的反应。最后，在G269 S中的磷酸化模拟物取代没有显示出增加IKs.Conclusions在对照条件下，G269 S适度影响IKs，但它几乎完全钝化IKs的反应性在模拟或模仿PKA磷酸化KCNQ 1的条件。这种对PKA刺激的不敏感性可能解释了为什么G269 S突变患者在运动时表现出QT间期过度延长。(C)2014年美国心脏病学会基金会
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 (I-Ks) 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. (C) 2014 by the American College of Cardiology Foundation