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* Center for Cardiovascular Bioinformatics and Modeling, The Whitaker Biomedical Engineering Institute, Department of Medicine Division of Cardiology, and ¶ The Institute for Molecular Cardiobiology, The Johns Hopkins University School of Medicine and Whiting School of Engineering, Baltimore, Maryland
Correspondence: Address reprint requests to Antti Tanskanen, The Johns Hopkins University, Clark Hall, Rm. 204, 3400 N. Charles St., Baltimore, MD 21218. E-mail: atanskan{at}bme.jhu.edu.
Certain signaling events that promote L-type Ca2+ channel (LCC) phosphorylation, such as ß-adrenergic stimulation or an increased expression of Ca2+/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 ß-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.
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