Trafficking-competent KCNQ1 variably influences the function of HERG long QT alleles.
Trafficking-competent KCNQ1 variably influences the function of HERG long QT alleles.
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DOI：
10.1016/j.hrthm.2010.03.038
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发表时间：
2010-07
期刊：
影响因子：
5.5
通讯作者：
Kupershmidt, Sabina
中科院分区：
文献类型：
--
作者：
Hayashi, Kenshi;Wen Shuai;Sakamoto, Yuichiro;Higashida, Haruhiro;Yamagishi, Masakazu;Kupershmidt, Sabina
KCNQ 1和HERG基因突变分别导致心脏复极化IKs和IKr电流减少，从而导致长QT Syndrome，LQTS 1和LQTS 2。先前报道，KCNQ 1共表达通过增强HERG的膜表达来调节HERG功能，并且这两种蛋白质共免疫沉淀并共定位于肌细胞中。在转基因兔中的体内研究也支持HERG-KCNQ 1相互作用。我们试图确定KCNQ 1是否影响HERG遗传变异的当前特征。HERG和KCNQ 1野生型（WT）和突变型通道在异源系统中的表达，结合全细胞膜片钳分析和生物化学。支持的概念，KCNQ 1需要有能力影响HERG功能的运输，我们发现，虽然在CHO细胞中表达的HERG的尾电流密度约为野生型KCNQ 1共表达的两倍，它并没有改变的存在下的运输缺陷KCNQ 1 T587 M变体。HERG变体的激活和失活动力学未改变。HERGM 124 T变异体，先前显示为轻度功能受损，通过KCNQ 1-WT而不是KCNQ 1 T587 M共表达恢复到WT水平。KCNQ 1共表达仅略微改善了严重运输受损的HERGG 601 S和HERGF 805 C变体的尾电流密度。有运输能力但未完全加工的HERGN 598 Q和选择性过滤器中的突变HERGG 628 S未通过KCNQ 1共表达得到改善。这些发现表明，在通道生物发生过程中HERG对KCNQ 1的功能性共依赖性。此外，KCNQ 1可调节具有不同潜在病理的LQTS 2突变。
Mutations in the KCNQ1 and HERG genes cause the Long QT Syndromes, LQTS1 and LQTS2, due to reductions in the cardiac repolarizing IKs and IKr currents, respectively. It was previously reported that KCNQ1 co-expression modulates HERG function by enhancing membrane expression of HERG, and that the two proteins co-immunoprecipitate, and co-localize in myocytes. In vivo studies in genetically modified rabbits also support a HERG-KCNQ1 interaction. We sought to determine whether KCNQ1 influences the current characteristics of HERG genetic variants. Expression of HERG and KCNQ1 wild type (WT) and mutant channels in heterologous systems, combined with whole cell patch clamp analysis and biochemistry. Supporting the notion that KCNQ1 needs to be trafficking competent to influence HERG function, we found that although the tail current density of HERG expressed in CHO cells was approximately doubled by WT KCNQ1 co-expression, it was not altered in the presence of the trafficking-defective KCNQ1T587M variant. Activation and deactivation kinetics of HERG variants were not altered. The HERGM124T variant, previously shown to be mildly impaired functionally, was restored to WT levels by KCNQ1-WT but not KCNQ1T587M co-expression. The tail current densities of the severely trafficking-impaired HERGG601S and HERGF805C variants were only slightly improved by KCNQ1 co-expression. The trafficking competent, but incompletely processed HERGN598Q, and a mutation in the selectivity filter, HERGG628S, were not improved by KCNQ1 co-expression. These findings suggest a functional co-dependence of HERG on KCNQ1 during channel biogenesis. Moreover, KCNQ1 variably modulates LQTS2 mutations with distinct underlying pathologies.
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