Properties of KvLQT1 K+ channel mutations in Romano-Ward and Jervell and Lange-Nielsen inherited cardiac arrhythmias
Properties of KvLQT1 K+ channel mutations in Romano-Ward and Jervell and Lange-Nielsen inherited cardiac arrhythmias
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DOI：
10.1093/emboj/16.17.5472
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发表时间：
1997-09-01
期刊：
影响因子：
11.4
通讯作者：
Barhanin, J
中科院分区：
文献类型：
--
作者：
Chouabe, C;Neyroud, N;Barhanin, J
延迟整流钾离子通道亚基KvLQT 1的突变已被确定为与Romano-Ward（RW）和Jervell和Lange-Nielsen（JLN）遗传性长QT综合征有关。我们报道了在包括心脏在内的几种人体组织中表达的人KvLQT 1亚型的分子克隆。表达研究表明KvLQT 1与另一个亚基IsK，重构了一个负责心室肌细胞复极过程中I-Ks电流的通道，产生了6个RW和2个JLN突变的KvLQT 1亚基，并在COS细胞中与IsK共表达。除R555 C外，当与野生型亚基共表达时，不能产生功能性同源通道并降低K+电流。因此，在这两种综合征中，突变的主要作用是KvLQT 1功能的显性负抑制。JLN突变具有较小的显性负效应，与疾病是隐性的事实一致。R555 C亚基在与IsK一起表达时形成功能通道，但具有改变的门控特性。激活的电压依赖性强烈地向更正值转移，并且失活动力学被加速。这一发现表明KvLQT结构的小的带正电荷的胞质区域的功能重要性，其中已经发现发生两个RW和一个JLN突变。
Mutations in the delayed rectifier K+ channel subunit KvLQT1 have been identified as responsible for both Romano-Ward (RW) and Jervell and Lange-Nielsen (JLN) inherited long QT syndromes, We report the molecular cloning of a human KvLQT1 isoform that is expressed in several human tissues including heart, Expression studies revealed that the association of KvLQT1 with another subunit, IsK, reconstitutes a channel responsible for the I-Ks current involved in ventricular myocyte repolarization, Six RW and two JLN mutated KvLQT1 subunits were produced and co-expressed with IsK in COS cells, All the mutants? except R555C, fail to produce functional homomeric channels and reduce the K+ current when co-expressed with the wild-type subunit. Thus, in both syndromes, the main effect of the mutations is a dominant-negative suppression of KvLQT1 function, The JLN mutations have a smaller dominant-negative effect, in agreement viith the fact that the disease is recessive, The R555C subunit forms a functional channel when expressed with IsK, but with altered gating properties, The voltage dependence of the activation is strongly shifted to more positive values, and deactivation kinetics are accelerated, This finding indicates the functional importance of a small positively charged cytoplasmic region of the KvLQT structure where two RW and one JLN mutations have been found to take place.