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首页> 美国卫生研究院文献>The Journal of Clinical Investigation >Functional role of inward rectifier current in heart probed by Kir2.1 overexpression and dominant-negative suppression
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Functional role of inward rectifier current in heart probed by Kir2.1 overexpression and dominant-negative suppression

机译：Kir2.1过表达和显性负抑制作用探查心脏内向整流电流的功能

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The inward rectifier current IK1 is tightly regulated regionally within the heart, downregulated in heart failure, and genetically suppressed in Andersen syndrome. We used in vivo viral gene transfer to dissect the role of IK1 in cardiac repolarization and maintenance of the resting membrane potential (RMP) in guinea pig ventricular myocytes. Kir2.1 overexpression boosted Ba2+-sensitive IK1 by more than 100% (at –50mV), significantly shortened action potential durations (APDs), accelerated phase 3 repolarization, and hyperpolarized RMP compared with control cells (nongreen cells from the same hearts and green cells from GFP-transduced hearts). The dominant-negative Kir2.1AAA reduced IK1 by 50–90%; those cells with less than 80% reduction of IK1 exhibited prolonged APDs, decelerated phase 3 repolarization, and depolarization of the RMP. Further reduction of IK1 resulted in a pacemaker phenotype, as previously described. ECGs revealed a 7.7% ± 0.9% shortening of the heart rate–corrected QT interval (QTc interval) in Kir2.1-transduced animals (n = 4) and a 16.7% ± 1.8% prolongation of the QTc interval (n = 3) in Kir2.1AAA-transduced animals 72 hours after gene delivery compared with immediate postoperative recordings. Thus, IK1 is essential for establishing the distinctive electrical phenotype of the ventricular myocyte: rapid terminal repolarization to a stable and polarized resting potential. Additionally, the long-QT phenotype seen in Andersen syndrome is a direct consequence of dominant-negative suppression of Kir2 channel function.
机译：内向整流器电流IK1在心脏内的区域受到严格调节，在心力衰竭时被下调，而在Andersen综合征中则受到基因抑制。我们使用体内病毒基因转移来剖析IK1在豚鼠心室肌​​细胞的心脏复极化和维持静息膜电位（RMP）中的作用。与对照细胞相比，Kir2.1过表达将Ba 2 + 敏感的IK1增强了100％以上（在–50mV），显着缩短了动作电位持续时间（APD），加速了3期复极化，并使RMP超极化。 （来自同一心脏的非绿色细胞和来自GFP转导的心脏的绿色细胞）。显性阴性的Kir2.1AAA使IK1降低了50–90％； IK1降低少于80％的那些细胞表现出延长的APD，减速的3期复极化和RMP复极化。如前所述，IK1的进一步降低导致起搏器表型。心电图显示，经Kir2.1转导的动物（n = 4）的心率校正QT间隔（QTc间隔）缩短了7.7％±0.9％，QTc间隔延长了16.7％±1.8％（n = 3）与直接术后记录相比，在基因递送72小时后，Kir2.1AAA转导的动物中的动物。因此，IK1对于建立独特的心室肌细胞电表型是必不可少的：快速终端复极化至稳定和极化的静息电位。此外，在Andersen综合征中看到的长QT表型是Kir2通道功能显性负抑制的直接结果。

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