Phosphoinositide 3-kinase ? protects against catecholamine-induced ventricular arrhythmia through protein kinase A-mediated regulation of distinct phosphodiesterases.

ABSTRACT: Phosphoinositide 3-kinase ? (PI3K?) signaling engaged by ?-adrenergic receptors is pivotal in the regulation of myocardial contractility and remodeling. However, the role of PI3K? in catecholamine-induced arrhythmia is currently unknown.Mice lacking PI3K? (PI3K?(-/-)) showed runs of premature ventricular contractions on adrenergic stimulation that could be rescued by a selective ?(2)-adrenergic receptor blocker and developed sustained ventricular tachycardia after transverse aortic constriction. Consistently, fluorescence resonance energy transfer probes revealed abnormal cAMP accumulation after ?(2)-adrenergic receptor activation in PI3K?(-/-) cardiomyocytes that depended on the loss of the scaffold but not of the catalytic activity of PI3K?. Downstream from ?-adrenergic receptors, PI3K? was found to participate in multiprotein complexes linking protein kinase A to the activation of phosphodiesterase (PDE) 3A, PDE4A, and PDE4B but not of PDE4D. These PI3K?-regulated PDEs lowered cAMP and limited protein kinase A-mediated phosphorylation of L-type calcium channel (Ca(v)1.2) and phospholamban. In PI3K?(-/-) cardiomyocytes, Ca(v)1.2 and phospholamban were hyperphosphorylated, leading to increased Ca(2+) spark occurrence and amplitude on adrenergic stimulation. Furthermore, PI3K?(-/-) cardiomyocytes showed spontaneous Ca(2+) release events and developed arrhythmic calcium transients.PI3K? coordinates the coincident signaling of the major cardiac PDE3 and PDE4 isoforms, thus orchestrating a feedback loop that prevents calcium-dependent ventricular arrhythmia.

SUBMITTER: Ghigo A 

PROVIDER: S-EPMC3913165 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature