Lv Jinhua, Jiang Yangxin, Zeng Jin, Zuo Dongchuan
Institute of Cardiovascular Research, Key Laboratory of Medical Electrophysiology, Ministry of Education, Southwest Medical University, 646000 Luzhou, Sichuan, China.
Department of Orthodontics, The Affiliated Stomatology Hospital of Southwest Medical University, 646000 Luzhou, Sichuan, China.
Front Biosci (Landmark Ed). 2025 Jul 24;30(7):39879. doi: 10.31083/FBL39879.
Hypokalemia induces abnormal spontaneous pacemaker activities of cardiomyocytes, which is strongly associated with fatal cardiac arrhythmias caused by hypokalemia. However, the mechanism remains unclear.
For the study of the mechanisms associated with hypokalemia, optical mapping recordings were performed on isolated murine hearts perfused with hypokalemia solutions, which allows for the concurrent examination of membrane potential and calcium transient morphology and arrhythmogenesis. Human Kir2.1, Kir2.1-E224G mutant, or Kir4.1 channels were constructed with lentiviral vectors. Patch clamp recordings were performed to verify the corresponding currents of these constructed channels in the heterologous expression system chinese hamster ovary (CHO) cells, and to explore how Kir2.1 channels influence the resting membrane potentials of human iPSC-derived cardiomyocytes (hiPSC-CMs) when exposed to low [K].
Isolated murine hearts perfused with hypokalemia solution (1 mmol/L) developed a high frequency of spontaneous ventricular tachycardia (VT), which was initiated as an after-depolarization triggered activity associated with Ca overload. The VT was maintained by abnormal spontaneous pacemaker activities caused by membrane potential depolarization. In response to 1 mmol/L [K], hiPSC-CMs overexpressing Kir2.1 channels exhibited membrane potential depolarization, leading to the induction of abnormal pacemaker activities. The cells overexpressing rectification-deficient Kir2.1-E224G mutant channels or weak rectification Kir4.1 channels exhibited membrane potential hyperpolarization without the occurrence of abnormal pacemaker activities.
Kir2.1 channel-mediated membrane potential depolarization contributes to hypokalemia-induced abnormal spontaneous pacemaker activities of cardiomyocytes. The inward rectification of Kir2.1 channels plays a critical role in this process.
低钾血症可诱导心肌细胞出现异常的自发起搏活动，这与低钾血症所致的致命性心律失常密切相关。然而，其机制尚不清楚。
为研究与低钾血症相关的机制，对用低钾血症溶液灌注的离体小鼠心脏进行光学标测记录，这使得能够同时检查膜电位、钙瞬变形态和心律失常的发生机制。用慢病毒载体构建人Kir2.1、Kir2.1-E224G突变体或Kir4.1通道。进行膜片钳记录以验证这些构建通道在异源表达系统中国仓鼠卵巢（CHO）细胞中的相应电流，并探讨Kir2.1通道在暴露于低钾[K]时如何影响人诱导多能干细胞衍生的心肌细胞（hiPSC-CMs）的静息膜电位。
用低钾血症溶液（1 mmol/L）灌注的离体小鼠心脏出现高频自发性室性心动过速（VT），其起始为与钙超载相关的后去极化触发活动。VT由膜电位去极化引起的异常自发起搏活动维持。在1 mmol/L [K]刺激下，过表达Kir2.1通道的hiPSC-CMs表现出膜电位去极化，导致异常起搏活动的诱导。过表达整流缺陷型Kir2.1-E224G突变体通道或弱整流Kir4.1通道的细胞表现出膜电位超极化，未出现异常起搏活动。
Kir2.1通道介导的膜电位去极化导致低钾血症诱导的心肌细胞异常自发起搏活动。Kir2.1通道的内向整流在此过程中起关键作用。
