β-adrenergic stimulation activates early afterdepolarizations transiently via kinetic mismatch of PKA targets.

ABSTRACT: Sympathetic stimulation regulates cardiac excitation-contraction coupling in hearts but can also trigger ventricular arrhythmias caused by early afterdepolarizations (EADs) in pathological conditions. Isoproterenol (ISO) stimulation can transiently cause EADs which could result from differential kinetics of L-type Ca current (ICaL) vs. delayed rectifier potassium current (IKs) effects, but multiple PKA targets complicate mechanistic analysis. Utilizing a biophysically detailed model integrating Ca and β-adrenergic signaling, we investigate how different phosphorylation kinetics and targets influence β-adrenergic-induced transient EADs. We found that: 1) The faster time course of ICaL vs. IKs increases recapitulates experimentally observed ISO-induced transient EADs (which are due to ICaL r

SUBMITTER: Xie Y 

PROVIDER: S-EPMC3628092 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature