Targeted deletion of kcne2 impairs ventricular repolarization via disruption of IK,slow1 and Ito,f
Targeted deletion of kcne2 impairs ventricular repolarization via disruption of IK,slow1 and Ito,f
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DOI：
10.1096/fj.08-110171
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发表时间：
2008-10-01
期刊：
影响因子：
4.8
通讯作者：
Abbott, Geoffrey W.
中科院分区：
文献类型：
--
作者：
Roepke, Torsten K.;Kontogeorgis, Andrianos;Abbott, Geoffrey W.
编码MiRP 1钾通道辅助亚基的人类KCNE 2突变与长QT综合征（LQTS）相关，这是一种心室复极缺陷。MiRP 1的确切心脏作用仍然存在争议，部分原因是它在体外具有显著的功能性混杂。在这里，我们破坏了小鼠kcne 2基因，以确定MiRP 1在小鼠心室中的作用。kcne 2破坏延长心室动作电位时程（APD），提示复极能力降低。因此，kcne 2（-/-）心室表现出I-K，I-slow 1减少50%，由Kv1.5产生-MiRP 1以前未知的伴侣。由Kv 4 α亚基产生的I-to，I-f也减少了约25%。心室MiRP 1蛋白与天然Kv1.5和Kv4.2共免疫沉淀，但不与Kv1.4或Kv4.3共免疫沉淀。出乎意料的是，kcne 2（-/-）心室膜组分显示出比野生型低50%的成熟Kv1.5蛋白，以及Kv1.5运输到闰盘的破坏。与心室K+电流减少和心室APD延长一致，在七氟烷麻醉下，kcne 2缺失延长了QT（c）。因此，靶向破坏kcne 2揭示了MiRP 1的新型心脏伴侣、MiRP在体内α亚基靶向中的新作用以及MiRP 1在小鼠心室复极中的作用，与人类心脏的作用相似。
Mutations in human KCNE2, which encodes the MiRP1 potassium channel ancillary subunit, associate with long QT syndrome (LQTS), a defect in ventricular repolarization. The precise cardiac role of MiRP1 remains controversial, in part, because it has marked functional promiscuity in vitro. Here, we disrupted the murine kcne2 gene to define the role of MiRP1 in murine ventricles. kcne2 disruption prolonged ventricular action potential duration (APD), suggestive of reduced repolarization capacity. Accordingly, kcne2 (-/-) ventricles exhibited a 50% reduction in I-K,I-slow1, generated by Kv1.5-a previously unknown partner for MiRP1. I-to,I-f, generated by Kv4 alpha subunits, was also diminished, by similar to 25%. Ventricular MiRP1 protein coimmunoprecipitated with native Kv1.5 and Kv4.2 but not Kv1.4 or Kv4.3. Unexpectedly, kcne2 (-/-) ventricular membrane fractions exhibited 50% less mature Kv1.5 protein than wild type, and disruption of Kv1.5 trafficking to the intercalated discs. Consistent with the reduction in ventricular K+ currents and prolonged ventricular APD, kcne2 deletion lengthened the QT(c) under sevoflurane anesthesia. Thus, targeted disruption of kcne2 has revealed a novel cardiac partner for MiRP1, a novel role for MiRPs in alpha subunit targeting in vivo, and a role for MiRP1 in murine ventricular repolarization with parallels to that proposed for the human heart.