The Role of Stochastic and Modal Gating of Cardiac L-Type Ca2+ Channels on Early After-Depolarizations

¹ Johns Hopkins University
² Johns Hopkins University School of Medicine
³ Johns Hopkins University School of Med. Whitaker Biomedical Engineering Institute

^* To whom correspondence should be addressed. E-mail: atanskan{at}bme.jhu.edu.

Submitted on August 17, 2004
Revised on September 15, 2004
Accepted on 5 October 2004

	Abstract

Certain signaling events which promote L-type Ca2+ channel (LCC) phosphorylation, such as beta-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 the ryanodine-sensitive calcium release channels. The model is extended to describe myocyte responses to the b-adrenergic agonist isoproterenol (ISO). Results demonstrate that in the presence of ISO 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.

Key Words: Early after-depolarization, L-type calcium channel, Mode 2 gating, Noise-induced transitions, Stochastic simulation, beta-Adrenergic Stimulation

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