Gain-of-function (GOF) mutations in the KCNQ1 voltage-gated potassium channel can induce cardiac arrhythmia. We tested whether any of the known GOF disease mutations in KCNQ1 act by increasing the amount of KCNQ1 that reaches the cell surface: super-trafficking. We found that levels of R231C KCNQ1 in the plasma membrane are 5-fold higher than wild type KCNQ1. This arises from both enhanced translocon-mediated membrane integration of the S4 voltage-sensor helix and an energetic linkage of C231 with the V129 and F166 side chains. Whole-cell electrophysiology recordings confirmed that R231C KCNQ1 in complex with KCNE1 is constitutively active, but also revealed the single channel activity of this mutant to be only 20% that of WT. The GOF phenotype associated with R231C therefore reflects the net effects of super-trafficking, reduced single channel activity, and constitutive channel activation. These investigations document membrane protein super-trafficking as a contributing mechanism to human disease.

中文翻译：

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疾病相关的突变钾通道的超级贩运

KCNQ1电压门控钾通道中的功能获得（GOF）突变可诱发心律不齐。我们测试了KCNQ1中任何已知的GOF疾病突变是否通过增加到达细胞表面的KCNQ1的数量起作用：超级贩运。我们发现，质膜中R231C KCNQ1的水平比野生型KCNQ1高5倍。这是由于增强的S4电压传感器螺旋的跨膜介导的膜整合以及C231与V129和F166侧链的能量连接所致。全细胞电生理学记录证实，与KCNE1结合的R231C KCNQ1具有组成性活性，但也显示该突变体的单通道活性仅为WT的20％。因此，与R231C相关的GOF表型反映了超级人口贩运的净效应，减少单通道活动和本构通道激活。这些研究证明了膜蛋白的过度贩运是导致人类疾病的一种机制。