The Role of Stochastic and Modal Gating of Cardiac L-Type Ca 2+ Channels on Early AfterDepolarizations

ABSTRACT Certainsignalingevents that promoteL-typeCa21 channel (LCC)phosphorylation, suchasb-adrenergic stimulation or an increased expression of Ca21/calmodulin-dependent protein kinase II, promote mode 2 gating of LCCs. Experimental data suggest thehypothesis that theseevents increase the likelihoodof 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 b-adrenergic agonist isoproterenol. Results demonstrate that in thepresenceof isoproterenol the randomopeningof a small numberof LCCsgating inmode2during theplateauphaseof 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 Ca21 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