Kv1.1 potassium channel subunit deficiency alters ventricular arrhythmia susceptibility, contractility, and repolarization.
Kv1.1 potassium channel subunit deficiency alters ventricular arrhythmia susceptibility, contractility, and repolarization.
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DOI：
10.14814/phy2.14702
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发表时间：
2021-01
影响因子：
2.5
通讯作者：
Glasscock E
中科院分区：
文献类型：
--
作者：
Trosclair K;Si M;Watts M;Gautier NM;Voigt N;Traylor J;Bitay M;Baczko I;Dobrev D;Hamilton KA;Bhuiyan MS;Dominic P;Glasscock E
传统上认为由 Kcna1 基因编码的癫痫相关 Kv1.1 电压门控钾通道亚基在心脏中不存在，但最近的研究表明它们在心肌细胞中表达，可以调节内在的心脏电生理学。尽管 Kv1.1 现在已在心房中发挥功能作用，但其在心室中的作用从未被研究过。在这项工作中，使用电生理学、组织学和基因表达方法在器官、细胞和分子水平上探讨 Kv1.1 缺陷对 Kcna1 敲除 (KO) 小鼠心室的影响，以确定 Kv1.1 的缺失是否会导致心室功能障碍，从而增加过早或猝死的风险。当进行心内起搏时，KO 小鼠对诱发性室性心律失常 (VA) 表现出正常的基线敏感性，但在异丙肾上腺素交感神经激发的条件下对 VA 表现出抵抗力。超声心动图显示心脏收缩功能障碍，表现为射血分数和缩短分数降低。在全细胞膜片钳记录中，KO 心室心肌细胞表现出动作电位延长，表明复极受损。成像、组织学和转录本分析显示没有结构或通道基因表达重塑的证据，这表明观察到的缺陷可能是由于 Kv1.1 缺陷所致。患者心脏样本的免疫印迹检测到 Kv1.1 的存在水平相对较高，这意味着 Kv1.1 有助于人类心脏电生理学。总而言之，这项工作描述了 Kv1.1 在心室中的重要功能作用，其缺失会导致复极和收缩性缺陷，但在交感神经驱动条件下降低心律失常的易感性。首次探索心室中 Kv1.1 通道的功能，揭示 Kv1.1 缺陷小鼠表现出对异丙肾上腺素起搏诱导的心律失常的抵抗力、超声心动图收缩性缺陷和潜在的动作电位延长，而没有结构或通道表达重塑的证据。患者心脏组织的免疫印迹显示人类心室中存在 Kv1.1 蛋白，表明其可能与人类健康和疾病有关。这些发现证明了 Kv1.1 在心室中的新作用，它影响心律失常的易感性、收缩性和复极。
Epilepsy‐associated Kv1.1 voltage‐gated potassium channel subunits encoded by the Kcna1 gene have traditionally been considered absent in heart, but recent studies reveal they are expressed in cardiomyocytes where they could regulate intrinsic cardiac electrophysiology. Although Kv1.1 now has a demonstrated functional role in atria, its role in the ventricles has never been investigated. In this work, electrophysiological, histological, and gene expression approaches were used to explore the consequences of Kv1.1 deficiency in the ventricles of Kcna1 knockout (KO) mice at the organ, cellular, and molecular levels to determine whether the absence of Kv1.1 leads to ventricular dysfunction that increases the risk of premature or sudden death. When subjected to intracardiac pacing, KO mice showed normal baseline susceptibility to inducible ventricular arrhythmias (VA) but resistance to VA under conditions of sympathetic challenge with isoproterenol. Echocardiography revealed cardiac contractile dysfunction manifesting as decreased ejection fraction and fractional shortening. In whole‐cell patch‐clamp recordings, KO ventricular cardiomyocytes exhibited action potential prolongation indicative of impaired repolarization. Imaging, histological, and transcript analyses showed no evidence of structural or channel gene expression remodeling, suggesting that the observed deficits are likely electrogenic due to Kv1.1 deficiency. Immunoblots of patient heart samples detected the presence of Kv1.1 at relatively high levels, implying that Kv1.1 contributes to human cardiac electrophysiology. Taken together, this work describes an important functional role for Kv1.1 in ventricles where its absence causes repolarization and contractility deficits but reduced susceptibility to arrhythmia under conditions of sympathetic drive. The functions of Kv1.1 channels in ventricles were explored for the first time revealing that Kv1.1‐deficient mice exhibit resistance to pacing‐induced arrhythmias with isoproterenol, echocardiographic contractility deficits, and underlying action potential prolongation without evidence of structural or channel expression remodeling. Immunoblots of cardiac tissue from patients revealed Kv1.1 protein in human ventricles, suggesting potential involvement in human health and disease. These findings demonstrate new roles for Kv1.1 in the ventricles where it influences arrhythmia susceptibility, contractility, and repolarization.
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影响因子：
4
作者：
Heijman, Jordi;Voigt, Niels;Dobrev, Dobromir
通讯作者：
Dobrev, Dobromir
DOI：
10.1016/j.yebeh.2013.09.019
发表时间：
2014-09
期刊：
Epilepsy & behavior : E&B
影响因子：
--
作者：
Glasscock E
通讯作者：
Glasscock E
影响因子：
5.6
作者：
Simeone KA;Hallgren J;Bockman CS;Aggarwal A;Kansal V;Netzel L;Iyer SH;Matthews SA;Deodhar M;Oldenburg PJ;Abel PW;Simeone TA
通讯作者：
Simeone TA
影响因子：
2
作者：
Morita N;Mandel WJ;Kobayashi Y;Karagueuzian HS
通讯作者：
Karagueuzian HS
影响因子：
5.4
作者：
Alam S;Abdullah CS;Aishwarya R;Miriyala S;Panchatcharam M;Peretik JM;Orr AW;James J;Robbins J;Bhuiyan MS
通讯作者：
Bhuiyan MS