Impaired stretch modulation in potentially lethal cardiac sodium channel mutants
Impaired stretch modulation in potentially lethal cardiac sodium channel mutants
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DOI：
10.4161/chan.4.1.10260
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发表时间：
2010-01-01
期刊：
影响因子：
3.3
通讯作者：
Morris, Catherine E.
中科院分区：
文献类型：
--
作者：
Banderali, Umberto;Juranka, Peter F.;Morris, Catherine E.
心脏钠通道 (hNa(V)1.5) 的两种缓慢失活突变体 R1623Q 和 R1626p 的存在与散发性长 QT3 (LQT3) 综合征相关，并可能导致室性快速心律失常和/或致命性心室紊乱。心脏机械电反馈被认为是这种偶发性心律失常的一个因素。由于拉伸力和剪切力调节 hNa(V)1.5 门控，LQT-Na(V)1.5 突变体通道亚基的详细电生理学研究可能会提供见解。我们比较了对照中的重组 R1623Q 和 WT 电流与非洲爪蟾卵母细胞贴壁斑块拉伸膜的电流。在移液管抽吸引起的拉伸之前、期间和之后监测宏观电流。在任一突变型 Na+ 通道中，小去极化时的峰值电流可通过拉伸增加一倍以上。与 WT 一样，R1623Q 在所有电压下都表现出可逆且与拉伸强度相关的电流起始和衰减加速，并且在拉伸过程中保留了这两个过程之间的动力学耦合。这两个 Na(V)1.5 通道 α 亚基在给定拉伸强度下的运动加速度的绝对范围上有所不同；在一定强度范围内，R1623Q 失活速度的增加显着低于 WT。 LQT3 突变体 R1626P 在拉伸过程中也保留了其动力学耦合。虽然 WT 拉伸差异电流（无拉伸的 I-Na(V,t) 减去有拉伸的 I-Na(V,t)）主要是抑制性的（相当于外向电流），但它们对 LQT3 突变体基本上 (R1623Q) 或完全 (R1626p) 是兴奋性的。如果拉伸调制 Na(V)1.5 电流（即短暂激励后加速电流衰减）通常有助于心脏机械电反馈，那么在血流动力学负荷变化期间，R1623Q 和 R1626p 电流的异常拉伸调制分量可能会导致心律失常。
The presence of two slowly inactivating mutants of the cardiac sodium channel (hNa(V)1.5), R1623Q and R1626p, associate with sporadic Long-QT3 (LQT3) syndrome, and may contribute to ventricular tachyarrhythmias and/or lethal ventricular disturbances. Cardiac mechanoelectric feedback is considered a factor in such sporadic arrhythmias. since stretch and shear forces modulate hNa(V)1.5 gating, detailed electrophysiological study of LQT-Na(V)1.5 mutant channel a subunit(s) might provide insights. We compared recombinant R1623Q and WT currents in control vs. stretched membrane of cell-attached patches of Xenopus oocytes. Macroscopic current was monitored before, during, and after stretch induced by pipette suction. In either mutant Na+ channel, peak current at small depolarizations could be more than doubled by stretch. as in WT, R1623Q showed reversible and stretch intensity dependent acceleration of current onset and decay at all voltages, with kinetic coupling between these two processes retained during stretch. These two Na(V)1.5 channel alpha subunits differed in the absolute extent of kinetic acceleration for a given stretch intensity; over a range of intensities, R1623Q inactivation speed increased significantly less than did WT. The LQT3 mutant R1626P also retained its kinetic coupling during stretch. Whereas WT stretch-difference currents (I-Na(V,t) without stretch minus I-Na(V,t) with stretch) were mostly inhibitory (equivalent to outward current), they were substantially (R1623Q) or entirely (R1626p) excitatory for the LQT3 mutants. If stretch-modulated Na(V)1.5 current (i.e., brief excitation followed by accelerated current decay) routinely contributes to cardiac mechanoelectric feedback, then during hemodynamic load variations, the abnormal stretch- modulated components of R1623Q and R1626p current could be pro-arrhythmic.