title: The role of stochastic and modal gating of cardiac L-type Ca2+ channels on early after-depolarizations.
abstract: 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.
authors.affiliation: Center for Cardiovascular Bioinformatics and Modeling, The Johns Hopkins University School of Medicine and Whiting School of Engineering, Baltimore, Maryland 21218, USA. atanskan@bme.jhu.edu
authors.forename: Antti J
authors.initials: AJ
authors.lastname: Tanskanen
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Greenstein
authors.forename: Brian
authors.initials: B
authors.lastname: O'Rourke
authors.forename: Raimond L
authors.initials: RL
authors.lastname: Winslow
mesh_terms: D000200:Action Potentials; D000465:Algorithms; D000818:Animals; D001703:Biophysics / Q000379:methods*; D002118:Calcium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000737:chemistry* / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D004285:Dogs; D004594:Electrophysiology; D006168:Guinea Pigs; D007477:Ions; D007545:Isoproterenol / Q000494:pharmacology; D008390:Markov Chains; D008564:Membrane Potentials; D008954:Models, Biological; D032342:Muscle Cells / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D010766:Phosphorylation; D012433:Ryanodine / Q000494:pharmacology; D015398:Signal Transduction; D013269:Stochastic Processes; D013997:Time Factors
chemical_list: D020746:Calcium Channels, L-Type; D007477:Ions; D012433:Ryanodine; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D007545:Isoproterenol; D002118:Calcium