PI3Kγ Protects against Catecholamine-Induced Ventricular Arrhythmia through PKA-mediated Regulation of Distinct Phosphodiesterases

Background —Phosphoinositide 3-kinase γ (PI3Kγ) signaling engaged by β-adrenergic receptors (β-ARs) is pivotal in the regulation of myocardial contractility and remodelling. However, the role of PI3Kγ in catecholamine-induced arrhythmia is presently unknown. Methods and Results —Mice lacking PI3Kγ(PI3Kγ -/- ) showed runs of premature ventricular contractions upon adrenergic stimulation, which could be rescued by a selective β 2 -AR blocker, and developed sustained ventricular tachycardia after transverse aortic constriction. Consistently, FRET probes revealed abnormal cAMP accumulation following β 2 -AR activation in PI3Kγ -/- cardiomyocytes, which depended on the loss of the scaffold but not of the catalytic activity of PI3Kγ. Downstream from β-ARs, PI3Kγ was found to participate in multi-protein complexes linking protein kinase A (PKA) to the activation of phosphodiesterases PDE3A, PDE4A and PDE4B, but not of PDE4D. These PI3Kγ-regulated PDEs lowered cAMP and limited PKA-mediated phosphorylation of L-type calcium channel (Ca v 1.2) and phospholamban (PLB). In PI3Kγ -/- cardiomyocytes, Ca v 1.2 and PLB were hyper-phosphorylated, leading to increased Ca 2+ spark occurrence and amplitude upon adrenergic stimulation. Furthermore, PI3Kγ -/- cardiomyocytes showed spontaneous Ca 2+ release events and developed arrhythmic calcium transients. Conclusions —PI3Kγ coordinates the coincident signalling of the major cardiac PDE3 and PDE4 isoforms, thus orchestrating a feedback loop that prevents calcium-dependent ventricular arrhythmia.