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Ca/calmodulin-dependent kinase II-dependent regulation of atrial myocyte late Na current, Ca cycling, and excitability: a mathematical modeling study. | LitMetric

AI Article Synopsis

Article Abstract

Atrial fibrillation (AF) affects more than three million people per year in the United States and is associated with high morbidity and mortality. Both electrical and structural remodeling contribute to AF, but the molecular pathways underlying AF pathogenesis are not well understood. Recently, a role for Ca/calmodulin-dependent protein kinase II (CaMKII) in the regulation of persistent "late" Na current ( I) has been identified. Although I inhibition is emerging as a potential antiarrhythmic strategy in patients with AF, little is known about the mechanism linking I to atrial arrhythmogenesis. A computational approach was used to test the hypothesis that increased CaMKII-activated I in atrial myocytes disrupts Ca homeostasis, promoting arrhythmogenic afterdepolarizations. Dynamic CaMKII activity and regulation of multiple downstream targets [ I, L-type Ca current, phospholamban, and the ryanodine receptor sarcoplasmic reticulum Ca-release channel (RyR2)] were incorporated into an existing well-validated computational model of the human atrial action potential. Model simulations showed that constitutive CaMKII-dependent phosphorylation of Na1.5 and the subsequent increase in I effectively disrupt intracellular atrial myocyte ion homeostasis and CaMKII signaling. Specifically, increased I promotes intracellular Ca overload via forward-mode Na/Ca exchange activity, which greatly increases RyR2 open probability beyond that observed for CaMKII-dependent phosphorylation of RyR2 alone. Increased I promotes atrial myocyte repolarization defects (afterdepolarizations and alternans) in the setting of acute β-adrenergic stimulation. We anticipate that our modeling efforts will help identify new mechanisms for atrial Na1.5 regulation with direct relevance for human AF. NEW & NOTEWORTHY Here, we present a novel computational model to study the effects of late Na current ( I) in human atrial myocytes. Simulations predict that I promotes intracellular accumulation of Ca, with subsequent dysregulation of Ca/calmodulin-dependent protein kinase II (CaMKII) signaling and ryanodine receptor 2-mediated Ca release. Although I plays a small role in regulating atrial myocyte excitability at baseline, CaMKII-dependent enhancement of the current promoted arrhythmogenic dynamics. Listen to this article's corresponding podcast at http://ajpheart.podbean.com/e/camkii-dependent-regulation-of-atrial-late-sodium-current-and-excitability/ .

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5814646PMC
http://dx.doi.org/10.1152/ajpheart.00185.2017DOI Listing

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