Manipulation of KCNE2 expression modulates action potential duration and Ito and IK in rat and mouse ventricular myocytes
Manipulation of KCNE2 expression modulates action potential duration and Ito and IK in rat and mouse ventricular myocytes
复制标题
操纵 KCNE2 表达可调节大鼠和小鼠心室肌细胞的动作电位持续时间以及 I-to 和 I-K
DOI：
10.1152/ajpheart.00757.2014
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发表时间：
2015-10-15
影响因子：
4.8
通讯作者：
Liu, Jie
中科院分区：
文献类型：
--
作者：
Liu, Wen-juan;Deng, Jian-xin;Liu, Jie
在异源表达系统中，KCNE2已被证明与电压依赖性阳离子通道的多个α亚基相互作用并调节其功能。然而，KCNE2在心肌细胞中的生理和病理作用尚不清楚。本研究旨在探讨双向调节KCNE2表达对心肌细胞动作电位（AP）持续时间（APD）和电压依赖性K+通道的影响。腺病毒基因传递和RNA干扰可增加或降低培养的新生大鼠和成年大鼠或新生小鼠心室肌细胞中KCNE2的表达。KCNE2敲低会延长新生儿和成人肌细胞的APD，而KCNE2过表达会缩短新生儿肌细胞的APD，但不会缩短成人肌细胞的APD。与APD的变化一致，KCNE2敲低降低了新生儿和成人肌细胞的瞬时外向K+电流（I-to）密度，而KCNE2过表达增加了新生儿肌细胞的Ito密度，但没有增加成人肌细胞的Ito密度。此外，KCNE2敲低加速了Ito激活和失活的速率，而KCNE2过表达减慢了新生肌细胞的Ito门控动力学，而不是成人肌细胞。KCNE2表达对小鼠延迟整流器K+电流密度有显著影响，而对大鼠心肌细胞无影响。用数学模型模拟大鼠心室肌细胞的AP表明，Ito密度和门控特性的改变可以导致KCNE2过表达和敲低细胞中类似的APD改变。综上所述，心肌细胞内源性KCNE2主要通过调节Ito和APD在维持心电稳定性中起重要作用。KCNE2表达的扰动可能通过延长APD使心脏易发生室性心律失常。
In heterologous expression systems, KCNE2 has been demonstrated to interact with multiple alpha-subunits of voltage-dependent cation channels and modulate their functions. However, the physiological and pathological roles of KCNE2 in cardiomyocytes are poorly understood. The present study aimed to investigate the effects of bidirectional modulation of KCNE2 expression on action potential (AP) duration (APD) and voltage-dependent K+ channels in cardiomyocytes. Adenoviral gene delivery and RNA interference were used to either increase or decrease KCNE2 expression in cultured neonatal and adult rat or neonatal mouse ventricular myocytes. Knockdown of KCNE2 prolonged APD in both neonatal and adult myocytes, whereas overexpression of KCNE2 shortened APD in neonatal but not adult myocytes. Consistent with the alterations in APD, KCNE2 knockdown decreased transient outward K+ current (I-to) densities in neonatal and adult myocytes, whereas KCNE2 overexpression increased Ito densities in neonatal but not adult myocytes. Furthermore, KCNE2 knockdown accelerated the rates of Ito activation and inactivation, whereas KCNE2 overexpression slowed Ito gating kinetics in neonatal but not adult myocytes. Delayed rectifier K+ current densities were remarkably affected by manipulation of KCNE2 expression in mouse but not rat cardiomyocytes. Simulation of the AP of a rat ventricular myocyte with a mathematical model showed that alterations in Ito densities and gating properties can result in similar APD alterations in KCNE2 overexpression and knockdown cells. In conclusion, endogenous KCNE2 in cardiomyocytes is important in maintaining cardiac electrical stability mainly by regulating Ito and APD. Perturbation of KCNE2 expression may predispose the heart to ventricular arrhythmia by prolonging APD.