低钾血症中双孔钾离子通道KCNK1诱发恶性心律失常的分子机制研究

低钾血症是临床上最为常见的电解质紊乱，可诱发恶性心律失常，但其致病机制目前还不清楚。作为心肌细胞膜上最新发现的一类背景钾通道，双孔钾离子通道KCNK1参与维持静息膜电位，但其在心肌细胞中的功能也不明确。我们前期工作发现KCNK1在低钾环境中会改变离子选择性并传导内向钠漏电流，导致细胞电兴奋性异常。据此我们提出科学假说：KNCK1钾通道在低钾状态下通过介导内向钠漏电流，造成心肌细胞静息膜电位异常去极化或电兴奋性异常，进而诱发心律失常甚至心源性猝死。鉴于小鼠心脏不表达KCNK1，我们构建了可诱导的心脏特异性过表达KCNK1基因工程小鼠，计划应用动物实验、细胞电生理和分子生物学实验探讨KCNK1在活体、器官和急性分离心肌细胞水平上是如何参与静息膜电位和心电活动异常、诱发心律失常甚至心源性猝死的致病分子和细胞机制。本研究为探索低钾血症诱发恶性心律失常提供新的理论基础，为临床治疗提供新的靶点和思路。

Hypokalemia is the most common electrolyte disorders in clinical, it is also one of the major causes of life-threatening cardiac arrhythmias, however, the underlying pathogenic mechanisms are still elusive. As a newly discovered background potassium channel in the human heart, KCNK1, the two pore-domain potassium channel member 1, participates in maintenance of resting membrane potential, but its role in human cardiomyocytes is not yet clear. Our previous studies have demonstrated that under hypokalemic conditions KCNK1 potassium channels dynamically change ion selectivity and switch to conduct inward leak sodium currents. Therefore, we hypothesize that hypokalemia-induced functional changes of KCNK1 channels induce aberrant resting membrane potential and impaired excitability of cardiomyocytes, which in turn results in cardiac arrhythmias and sudden cardiac death. Since mouse and rat hearts do not express KCNK1, we have created a transgenic mouse model that conditionally and specifically overexpresses KCNK1 in hearts. To test the hypothesis, we will use both transgenic mice and negative control mice to characterize function of KCNK1 in freshly isolated cardiomyocytes, in the isolated whole hearts, and in live animals, with cellular electrophysiology, molecular biology, and experimental zoology approaches. This study will not only significantly advance our understanding of the pathogenic mechanism of KCNK1 in hypokalemia-induced cardiac arrhythmias, but also provide a new path for diagnose and therapy for hypokalemia-induced cardiac arrhythmias.