Tanskanen Antti J, Greenstein Joseph L, O'Rourke Brian, Winslow Raimond L
Center for Cardiovascular Bioinformatics and Modeling, The Johns Hopkins University School of Medicine and Whiting School of Engineering, Baltimore, Maryland 21218, USA.
Biophys J. 2005 Jan;88(1):85-95. doi: 10.1529/biophysj.104.051508. Epub 2004 Oct 22.
Certain signaling events that promote L-type Ca2+ channel (LCC) phosphorylation, such as beta-adrenergic stimulation or an increased expression of Ca(2+)/calmodulin-dependent protein kinase II, promote mode 2 gating of LCCs. Experimental data suggest the hypothesis that these events increase the likelihood of early after-depolarizations (EADs). We test this hypothesis using an ionic model of the canine ventricular myocyte incorporating stochastic gating of LCCs and ryanodine-sensitive calcium release channels. The model is extended to describe myocyte responses to the beta-adrenergic agonist isoproterenol. Results demonstrate that in the presence of isoproterenol the random opening of a small number of LCCs gating in mode 2 during the plateau phase of the action potential (AP) can trigger EADs. EADs occur randomly, where the likelihood of these events increases as a function of the fraction of LCCs gating in mode 2. Fluctuations of the L-type Ca2+ current during the AP plateau lead to variability in AP duration. Consequently, prolonged APs are occasionally observed and exhibit an increased likelihood of EAD formation. These results suggest a novel stochastic mechanism, whereby phosphorylation-induced changes in LCC gating properties contribute to EAD generation.
某些促进L型钙通道（LCC）磷酸化的信号事件，如β-肾上腺素能刺激或钙/钙调蛋白依赖性蛋白激酶II表达增加，会促进LCC的模式2门控。实验数据提出了这样一个假设，即这些事件会增加早期后去极化（EAD）的可能性。我们使用包含LCC随机门控和雷诺丁敏感钙释放通道的犬心室肌细胞离子模型来检验这一假设。该模型被扩展以描述肌细胞对β-肾上腺素能激动剂异丙肾上腺素的反应。结果表明，在存在异丙肾上腺素的情况下，动作电位（AP）平台期少量以模式2门控的LCC随机开放可触发EAD。EAD随机发生，这些事件的可能性随着以模式2门控的LCC比例的增加而增加。AP平台期L型钙电流的波动导致AP持续时间的变异性。因此，偶尔会观察到延长的AP，并且其形成EAD的可能性增加。这些结果提示了一种新的随机机制，即磷酸化诱导的LCC门控特性变化有助于EAD的产生。
