TWIK-1与Kir2.1钾通道协同作用对低钾血症诱发的心肌细胞触发活动的机制研究

触发活动是低钾血症诱发心律失常的重要机制之一，但其发生的机理尚不完全清楚。我们前期的研究表明:低血钾时TWIK-1钾通道改变离子选择性并通透钠离子,当其传导的钠电流与Kir2.1钾通道传导的钾电流达到动态平衡时，协同作用会引起心肌细胞膜电位瞬时去极化。但低血钾诱发的心肌细胞触发活动的分子机制还有待进一步探讨。为此，我们推测，低血钾时TWIK-1与Kir2.1钾通道协同作用诱发心肌细胞触发活动的发生。为了验证这一假说，我们将通过人类干细胞诱导而来的心肌细胞模型，采用病毒载体转染，RNAi干扰，电生理，离子成像等手段，从分子和细胞水平来探讨TWIK-1与Kir2.1钾通道在低血钾诱发的心肌细胞触发活动中的作用；并观察TWIK-1钾通道功能的改变对心肌细胞内钙离子浓度的影响，以其阐明低钾血症诱发心肌细胞触发活动的分子机理。这一研究将为低钾血症诱发的心律失常的致病机制提供理论基础。

Triggered activity (TA) play an important role in hypokalemia-induced cardiac arrhythmias, and the mechanisms underlying the hypokalemia-induced Triggered activity is not completely understand. Our previous study showed that in hypokalemia TWIK-1 potassium channels change selectivity and become permeable to Na+. The Na+ currents carried by TWIK-1 potassium channels counterbalance to K+ currents carried by Kir2.1 channels, contributing to the transient membrane potential depolarization in cardiac myocytes. However, the mechanisms underlying the hypokalemia-induced Triggered activity still requires further investigation. For this purpose, we hypothesize that the counterbalance between TWIK-1 and Kir2.1 potassium channels contribute to the hypokalemia-induced Triggered activity. To test the hypothesize, we will employ the cardiomyocytes derived from human induced pluripotent stem cells (hiPSC-CMs )as the models of cardiac myocytes and with strategies in adenoviral vectors、RNAi、patch clamp、ion imaging to discuss the role of TWIK-1 and Kir2.1 potassium channels in hypokalemia-induced Triggered activity, and to observe the effects of functional changes of TWIK-1potassium channels on the intracellular Ga2+ concentration. The aim of this study is to illuminate the mechanisms underlying the hypokalemia-induced Triggered activity, and provide theory basis on etiology of hypokalemia induced arrhythmias.