Cellular dysfunction of LQT5-minK mutants:: abnormalities of IKs, IKr and trafficking in long QT syndrome
Cellular dysfunction of LQT5-minK mutants:: abnormalities of IKs, IKr and trafficking in long QT syndrome
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DOI：
10.1093/hmg/8.8.1499
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发表时间：
1999-08-01
影响因子：
3.5
通讯作者：
Brown, AM
中科院分区：
文献类型：
--
作者：
Bianchi, L;Shen, ZJ;Brown, AM
貂基因KCNE1的突变与人类长QT综合征的LQT5变异有关。MinK与KvLQT1组合产生慢速延迟整流器K+电流I-KS，并可与HERG组合调制快速延迟整流器I-Kr。我们采用电生理和免疫细胞化学方法比较了野生型水貂和4个与KvLQT1共表达的LQT5突变体在爪蟾卵母细胞中的细胞表型和HEK293细胞中的HERG。我们发现三个突变体V47F、W87R和D76N在细胞表面表达，而一个突变体L51H没有在细胞表面表达。与WT-minK相比，V47F和W87R与KvLQT1共表达产生了门控改变和幅度减小的I-Ks电流，与L51H共表达产生了KvLQT1电流而不是I-Ks电流，与D76N共表达抑制了KvLQT1电流。V47F增加了HERG电流，但作用程度低于WT-minK，而L51H和W87R没有作用，D76N明显抑制了HERG电流。由此可见，V47F与KvLQT1和HERG都有相互作用，W87R与KvLQT1有功能相互作用，但与HERG没有作用，D76N对KvLQT1和HERG都有抑制作用，而L51H处理不当，与两个通道都没有相互作用。我们得出结论，minK是I-Ks和I-Kr表达的辅助因子，并提出LQT5的临床表现可能因minK突变对KvLQT1和HERG的不同影响而复杂化。
Mutations in the minK gene KCNE1 have been linked to the LQT5 variant of human long QT syndrome. MinK assembles with KvLQT1 to produce the slow delayed rectifier K+ current I-KS and may assemble with HERG to modulate the rapid delayed rectifier I-Kr. We used electrophysiological and immunocytochemical methods to compare the cellular phenotypes of wild-type minK and four LQT5 mutants co-expressed with KvLQT1 in Xenopus oocytes and HERG in HEK293 cells. We found that three mutants, V47F, W87R and D76N, were expressed at the cell surface, while one mutant, L51H, was not. Coexpression of V47F and W87R with KvLQT1 produced I-Ks currents having altered gating and reduced amplitudes compared with WT-minK, co-expression with L51H produced KvLQT1 current rather than I-Ks and coexpression with D76N suppressed KvLQT1 current. V47F increased HERG current but to a lesser extent than WT-minK, while L51H and W87R had no effect and D76N suppressed HERG current markedly, Thus, V47F interacts with both KvLQT1 and HERG, W87R interacts functionally with KvLQT1 but not with HERG, D76N suppresses both KvLQT1 and HERG, and L51H is processed improperly and interacts with neither channel, We conclude that minK is a co-factor in the expression of both I-Ks and I-Kr and propose that clinical manifestations of LQT5 may be complicated by differing effects of minK mutations on KvLQT1 and HERG.