Long QT Syndrome-Associated Mutations in KCNQ1 and KCNE1 Subunits Disrupt Normal Endosomal Recycling of IKs Channels
Long QT Syndrome-Associated Mutations in KCNQ1 and KCNE1 Subunits Disrupt Normal Endosomal Recycling of IKs Channels
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DOI：
10.1161/circresaha.108.177360
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发表时间：
2008-12-05
影响因子：
20.1
通讯作者：
Lang, Florian
中科院分区：
文献类型：
--
作者：
Seebohm, Guiscard;Strutz-Seebohm, Nathalie;Lang, Florian
身体和情绪上的压力伴随着压力荷尔蒙的释放，比如糖皮质激素。这种激素上调血清和糖皮质激素诱导的可导性激酶(SGK)1，进而刺激I(Ks)，这是一种介导心脏动作电位复极的缓慢延迟整流钾电流。I(Ks)通道α(KCNQ1，KvLQT1，Kv7.1)或β(KCNE1，ISK，mink)亚单位的突变会导致长QT综合征(LQTS)，这是一种遗传性心律失常，与猝死的风险增加相关。SGK1与GTP酶RAB5和Rab11一起促进KCNQ1通道的膜再循环。在这里，我们展示了改变的SGK1依赖的调节LQTS相关的突变I(Ks)通道。一些突变的KCNQ1通道的基础活性降低，但仍可被SGK1激活，而由KCNQ1(Y111C)或KCNQ1(L114P)介导的电流却被SGK1反常地减弱。由野生型KCNQ1和LQTS相关的KCNE1(D76N)突变体共同组装的异构体通道类似地被SGK1下调，因为依赖Rab11的循环中断。诱变实验表明，SGK1对I(Ks)通道的刺激依赖于KCNE1中的H73、N75、D76和P77残基。识别I(Ks)循环途径及其被应激刺激的SGK1的调节为从机制上洞察由生理或心理应激引发的潜在致命性心律失常提供了新的机制。(中国保监会决议2008；103：1451-1457。)
Physical and emotional stress is accompanied by release of stress hormones such as the glucocorticoid cortisol. This hormone upregulates the serum-and glucocorticoid-inducible kinase (SGK)1, which in turn stimulates I(Ks), a slow delayed rectifier potassium current that mediates cardiac action potential repolarization. Mutations in I(Ks) channel alpha (KCNQ1, KvLQT1, Kv7.1) or beta (KCNE1, IsK, minK) subunits cause long QT syndrome (LQTS), an inherited cardiac arrhythmia associated with increased risk of sudden death. Together with the GTPases RAB5 and RAB11, SGK1 facilitates membrane recycling of KCNQ1 channels. Here, we show altered SGK1-dependent regulation of LQTS-associated mutant I(Ks) channels. Whereas some mutant KCNQ1 channels had reduced basal activity but were still activated by SGK1, currents mediated by KCNQ1(Y111C) or KCNQ1(L114P) were paradoxically reduced by SGK1. Heteromeric channels coassembled of wild-type KCNQ1 and the LQTS-associated KCNE1(D76N) mutant were similarly downregulated by SGK1 because of a disrupted RAB11-dependent recycling. Mutagenesis experiments indicate that stimulation of I(Ks) channels by SGK1 depends on residues H73, N75, D76, and P77 in KCNE1. Identification of the I(Ks) recycling pathway and its modulation by stress-stimulated SGK1 provides novel mechanistic insight into potentially fatal cardiac arrhythmias triggered by physical or psychological stress. (Circ Res. 2008;103:1451-1457.)