NCX-Mediated Subcellular Ca2+ Dynamics Underlying Early Afterdepolarizations in LQT2 Cardiomyocytes.
NCX-Mediated Subcellular Ca2+ Dynamics Underlying Early Afterdepolarizations in LQT2 Cardiomyocytes.
复制标题
NCX 介导的 LQT2 心肌细胞早期后去极化的亚细胞 Ca2 动力学。
DOI：
10.1016/j.bpj.2018.08.004
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发表时间：
2018
影响因子：
3.4
通讯作者：
Karma,Alain
中科院分区：
文献类型：
--
作者：
Zhong,Mingwang;Rees,ColinM;Terentyev,Dmitry;Choi,Bum-Rak;Koren,Gideon;Karma,Alain
长QT综合征2型（LQT 2）是一种以hERG钾通道（IKr）功能缺失突变为特征的先天性疾病。LQT 2与早期后除极（埃兹）形式的触发活动促进的致死性室性心律失常相关。我们以前证明，细胞内Ca 2+处理重塑LQT 2肌细胞。重构导致异常的晚期RyR介导的Ca 2+释放，其驱动正向模式Na+-Ca 2+交换器（NCX）电流并减慢复极化以促进L型钙通道和埃兹的重新开放。正向模式NCX被认为是增强，尽管事实上，这些后期释放不显着改变整个细胞胞浆钙浓度在一个脆弱的时期相对应的动作电位的发病埃兹的2。在这里，我们使用多尺度心室肌细胞模型来解释这一发现。我们发现，由于本地NCX电流是一个饱和的非线性函数的局部膜下钙离子浓度，大量的小振幅离散的Ca 2+释放事件可以产生一个大的增加全细胞前向模式NCX电流没有显着增加全细胞胞质钙离子浓度。此外，我们开发新的见解，据我们所知，如何改变随机RyR活性在单通道水平导致后期异常Ca 2+释放事件。在转基因LTQ 2兔中的实验测量证实了NCX的关键致瘤作用，并将该电流确定为LQT 2中抗肿瘤治疗的潜在靶点。
Long QT syndrome type 2 (LQT2) is a congenital disease characterized by loss of function mutations in hERG potassium channels (IKr). LQT2 is associated with fatal ventricular arrhythmias promoted by triggered activity in the form of early afterdepolarizations (EADs). We previously demonstrated that intracellular Ca2+handling is remodeled in LQT2 myocytes. Remodeling leads to aberrant late RyR-mediated Ca2+releases that drive forward-mode Na+-Ca2+exchanger (NCX) current and slow repolarization to promote reopening of L-type calcium channels and EADs. Forward-mode NCX was found to be enhanced despite the fact that these late releases do not significantly alter the whole-cell cytosolic calcium concentration during a vulnerable period of phase 2 of the action potential corresponding to the onset of EADs. Here, we use a multiscale ventricular myocyte model to explain this finding. We show that because the local NCX current is a saturating nonlinear function of the local submembrane calcium concentration, a larger number of smaller-amplitude discrete Ca2+release events can produce a large increase in whole-cell forward-mode NCX current without increasing significantly the whole-cell cytosolic calcium concentration. Furthermore, we develop novel insights, to our knowledge, into how alterations of stochastic RyR activity at the single-channel level cause late aberrant Ca2+release events. Experimental measurements in transgenic LTQ2 rabbits confirm the critical arrhythmogenic role of NCX and identify this current as a potential target for antiarrhythmic therapies in LQT2.