CaMKII-dependent activation of late INa contributes to cellular arrhythmia in a model of the cardiac myocyte.
CaMKII-dependent activation of late INa contributes to cellular arrhythmia in a model of the cardiac myocyte.
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在心肌细胞模型中，INA晚期的CAMKII依赖性激活有助于细胞心律失常。
DOI：
10.1109/iembs.2011.6091155
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发表时间：
2011
期刊：
影响因子：
--
通讯作者：
Greenstein JL
中科院分区：
文献类型：
--
作者：
Hashambhoy YL;Winslow RL;Greenstein JL
在动作电位（AP）上升过程中，心脏电压门控Na+通道是膜去极化的基础。这些通道也表现出晚期、缓慢失活的电流成分（晚期INa），在病理性条件下，如心力衰竭，可能会增强，因此可能促进AP延长，增加心律失常的可能性。Ca2+/钙调素依赖性蛋白激酶II （CaMKII）在功能上修饰Na+通道，然而，尚不清楚CaMKII依赖性晚期INa的变化是否是细胞心律失常的主要因素，如去极化后早期（EADs）。在这项研究中，我们建立了一个基于实验测量的INa模型，包括camkii依赖效应。Na+通道模型被纳入到整个心肌细胞的计算模型中，该模型通过随机模拟单个Ca2+释放位点来描述兴奋-收缩耦合。模拟表明，相对较小的后期INa增加足以显著延长APs并导致EADs的出现。
Cardiac voltage-gated Na+ channels underlie membrane depolarization during the upstroke of the action potential (AP). These channels also exhibit a late, slowly-inactivating component of current (late INa) that may be enhanced under pathological conditions such as heart failure, and may therefore promote AP prolongation and increase the likelihood of arrhythmia. Ca2+/calmodulin-dependent protein kinase II (CaMKII) functionally modifies Na+ channels, however it remains unclear if the CaMKII-dependent changes in late INa are a major contributor to cellular arrhythmias such as early after depolarizations (EADs). In this study we develop a model of INa, including CaMKII-dependent effects, based on experimental measurements. The Na+ channel model is incorporated into a computational model of the whole myocyte which describes excitation-contraction coupling via stochastic simulation of individual Ca2+ release sites. Simulations suggest that relatively small augmentation of late INa is sufficient to significantly prolong APs and lead to the appearance of EADs.