Arrhythmogenic钙调蛋白突变阻碍激活small-conductance calcium-activated钾电流。
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于CC, Ko JS, Ai T,蔡WC,陈Z, Rubart M, Vatta M,埃弗雷特TH 4日,乔治·艾尔·Jr陈PS
Arrhythmogenic钙调蛋白突变阻碍激活small-conductance calcium-activated钾电流。
心律。2016年8月13日(8):1716 - 23所示。doi: 10.1016 / j.hrthm.2016.05.009。2016年5月7日Epub。
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27165696 (在PubMed]
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背景:Apamin-sensitive small-conductance calcium-activated钾(SK)通道封闭了细胞内钙(2 +)通过本构与钙调蛋白的交互。目的:我们假设arrhythmogenic人钙调蛋白突变阻碍SK通道的激活。方法:我们研究了5以前公布的钙调蛋白突变(N54I, N98S, D96V、D130G F90L)。质粒编码野生型或突变体钙调蛋白是暂时性的转染293人类胚胎肾细胞稳定表达亚型2 SK蛋白通道(SK2细胞)。全细胞电压钳记录被用来确定apamin-sensitive电流密度。我们还执行光学映射研究在正常小鼠的心决定的影响apamin在心中(n = 7)或没有(n = 3)预处理与海葵毒素。结果:SK2细胞转染野生型钙调蛋白表现出一个apamin-sensitive电流密度为33.6 pA / pF (31.4 - -36.5 pA / pF)(和置信区间中值25 th - 75),明显高于观察细胞转染与N54I (17.0 pA / pF (14.0 - -27.7 pA / pF);P = .016), F90L (22.6 pA / pF (20.3 - -24.3 pA / pF);P = .011), D96V (13.0 pA / pF (10.9 - -15.8 pA / pF);P = .003), N98S (13.7 pA / pF (8.8 - -20.4 pA / pF); P = .005), and D130G (17.6 pA/pF [13.8-24.6 pA/pF]; P = .003). The decrease in SK2 current densities was not associated with a decrease in membrane protein expression or intracellular distribution of the channel protein. Apamin increased the ventricular action potential duration at 80% repolarization (from 79.6 ms [63.4-93.3 ms] to 121.8 ms [97.9-127.2 ms]; P = .010) in hearts pretreated with anemone toxin but not in control hearts. CONCLUSION: Human arrhythmogenic calmodulin mutations impede the activation of SK2 channels in human embryonic kidney 293 cells.