Genetic variation in the two-pore domain potassium channel, TASK-1, may contribute to an atrial substrate for arrhythmogenesis
Genetic variation in the two-pore domain potassium channel, TASK-1, may contribute to an atrial substrate for arrhythmogenesis
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DOI：
10.1016/j.yjmcc.2013.12.014
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发表时间：
2014-02-01
影响因子：
5
通讯作者：
Fatkin, Diane
中科院分区：
文献类型：
--
作者：
Liang, Bo;Soka, Magdalena;Fatkin, Diane
双孔结构域钾通道K（2P）3.1（ASK-1）调节离体人心房心肌细胞的背景电导，并已被提议作为心房颤动（AF）的潜在药物靶点。然而，Task-I敲除小鼠具有主要的心室表型，并且Task-I失活对心房结构和功能的影响尚未在体内证实。编码ASK-1的KCNK3的遗传变异在多大程度上可能是AF易感性的决定因素也是未知的。为了解决这些问题，我们首先评估了斑马鱼kcnk3a和kcnk3b基因瞬时敲低的影响，并使用视频显微镜评估了心脏表型。与对照注射胚胎相比，受精后72小时的胚胎中kcnk3a和kcnk3b联合敲低导致心率降低（p <0.001），心房直径显著增加（p <0.001），舒张末期心室直径轻度增加（p = 0.01）。接下来，我们在两个独立的AF队列（373例受试者）中进行了KCNK3的遗传筛查，并鉴定了三种新的KCNK3变体。其中两个变异体存在于一个家族性房颤先证者中，位于Kozak序列的相邻核苷酸处，并降低了工程报告基因的表达。第三个错义变体V123L在孤立性房颤患者中，在膜片钳实验中降低了静息膜电位并改变了pH敏感性，结构建模预测了在ASK-1孔附近的不稳定性。这些体外数据表明，双Kozak变体和V123L将对I-task心脏动作电位模型具有功能丧失效应，预测I-task心房动作电位持续时间缩短，并且这通过其他离子通道电流活性的相互变化而增强。我们的研究结果表明，I-task在心房的功能的重要性，并表明，task-1的失活可能有不同的影响心房的大小和电生理特性，可以有助于致心律失常的基板。(C)2014爱思唯尔有限公司版权所有。
The two-pore domain potassium channel, K(2P)3.1 (TASK-1) modulates background conductance in isolated human atrial cardiomyocytes and has been proposed as a potential drug target for atrial fibrillation (AF). TASK-1 knockout mice have a predominantly ventricular phenotype however, and effects of TASK-1 inactivation on atrial structure and function have yet to be demonstrated in vivo. The extent to which genetic variation in KCNK3, that encodes TASK-1, might be a determinant of susceptibility to AF is also unknown. To address these questions, we first evaluated the effects of transient knockdown of the zebrafish kcnk3a and kcnk3b genes and cardiac phenotypes were evaluated using videomicroscopy. Combined kcnk3a and kcnk3b knockdown in 72 hour post fertilization embryos resulted in lower heart rate (p < 0.001), marked increase in atrial diameter (p < 0.001), and mild increase in end-diastolic ventricular diameter (p = 0.01) when compared with control-injected embryos. We next performed genetic screening of KCNK3 in two independent AF cohorts (373 subjects) and identified three novel KCNK3 variants. Two of these variants, present in one proband with familial AF, were located at adjacent nucleotides in the Kozak sequence and reduced expression of an engineered reporter. A third missense variant, V123L, in a patient with lone AF, reduced resting membrane potential and altered pH sensitivity in patch-clamp experiments, with structural modeling predicting instability in the vicinity of the TASK-1 pore. These in vitro data suggest that the double Kozak variants and V123L will have loss-of-function effects on I-TASK Cardiac action potential modeling predicted that reduced I-TASK prolongs atrial action potential duration, and that this is potentiated by reciprocal changes in activity of other ion channel currents. Our findings demonstrate the functional importance of I-TASK in the atrium and suggest that inactivation of TASK-1 may have diverse effects on atrial size and electrophysiological properties that can contribute to an arrhythmogenic substrate. (C) 2014 Elsevier Ltd. All rights reserved.