Fatty acid analogue N-arachidonoyl taurine restores function of IKs channels with diverse long QT mutations
Fatty acid analogue N-arachidonoyl taurine restores function of IKs channels with diverse long QT mutations
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DOI：
10.7554/elife.20272
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发表时间：
2016-09-30
期刊：
影响因子：
7.7
通讯作者：
Larson, H. Peter
中科院分区：
文献类型：
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作者：
Liin, Sara I.;Larsson, Johan E.;Larson, H. Peter
在患有长QT综合征和心律失常的患者中已经确定了约300种I-Ks通道的功能丧失突变。特定突变如何导致心律失常在很大程度上是未知的，并且没有批准的I-Ks通道激活剂用于治疗这些心律失常。我们发现，几个长QT综合征相关的IKs通道突变改变通道电压依赖性和加速通道关闭。电压钳荧光实验和动力学建模表明，类似的突变诱导的IKs通道电流的改变可能是由不同的分子机制。最后，我们发现脂肪酸类似物N-花生四烯酰牛磺酸恢复了许多不同突变通道的通道门控，尽管这些突变位于IKs通道的不同结构域并通过不同的分子机制影响通道。因此，N-花生四烯酸牛磺酸是一种有趣的原型化合物，可能会激发未来IKs通道激活剂的开发，以治疗由不同IKs通道突变引起的长QT综合征。
About 300 loss-of-function mutations in the I-Ks channel have been identified in patients with Long QT syndrome and cardiac arrhythmia. How specific mutations cause arrhythmia is largely unknown and there are no approved I-Ks channel activators for treatment of these arrhythmias. We find that several Long QT syndrome-associated IKs channel mutations shift channel voltage dependence and accelerate channel closing. Voltage-clamp fluorometry experiments and kinetic modeling suggest that similar mutation-induced alterations in IKs channel currents may be caused by different molecular mechanisms. Finally, we find that the fatty acid analogue N-arachidonoyl taurine restores channel gating of many different mutant channels, even though the mutations are in different domains of the IKs channel and affect the channel by different molecular mechanisms. N-arachidonoyl taurine is therefore an interesting prototype compound that may inspire development of future IKs channel activators to treat Long QT syndrome caused by diverse IKs channel mutations.