title: CaMKII-dependent activation of late INa contributes to cellular arrhythmia in a model of the cardiac myocyte.
abstract: Cardiac voltage-gated Na(+) channels underlie membrane depolarization during the upstroke of the action potential (AP). These channels also exhibit a late, slowly-inactivating component of current (late I(Na)) that may be enhanced under pathological conditions such as heart failure, and may therefore promote AP prolongation and increase the likelihood of arrhythmia. Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) functionally modifies Na(+) channels, however it remains unclear if the CaMKII-dependent changes in late I(Na) are a major contributor to cellular arrhythmias such as early after depolarizations (EADs). In this study we develop a model of I(Na), including CaMKII-dependent effects, based on experimental measurements. The Na(+) channel model is incorporated into a computational model of the whole myocyte which describes excitation-contraction coupling via stochastic simulation of individual Ca(2+) release sites. Simulations suggest that relatively small augmentation of late I(Na) is sufficient to significantly prolong APs and lead to the appearance of EADs.
authors.affiliation: Department of Biomedical Engineering, Institute for Computational Medicine, TheJohns Hopkins University, Baltimore, MD 21218, USA. yhasham2@jhmi.e du
authors.forename: Yasmin L
authors.initials: YL
authors.lastname: Hashambhoy
authors.forename: Raimond L
authors.initials: RL
authors.lastname: Winslow
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Greenstein
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000378:metabolism*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D010766:Phosphorylation; D015222:Sodium Channels / Q000378:metabolism
chemical_list: D015222:Sodium Channels; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2