| First Author | Ghigo A | Year | 2012 |
| Journal | Circulation | Volume | 126 |
| Issue | 17 | Pages | 2073-83 |
| PubMed ID | 23008439 | Mgi Jnum | J:210072 |
| Mgi Id | MGI:5569466 | Doi | 10.1161/CIRCULATIONAHA.112.114074 |
| Citation | Ghigo A, et al. (2012) Phosphoinositide 3-kinase gamma protects against catecholamine-induced ventricular arrhythmia through protein kinase A-mediated regulation of distinct phosphodiesterases. Circulation 126(17):2073-83 |
| abstractText | BACKGROUND: Phosphoinositide 3-kinase gamma (PI3Kgamma) signaling engaged by beta-adrenergic receptors is pivotal in the regulation of myocardial contractility and remodeling. However, the role of PI3Kgamma in catecholamine-induced arrhythmia is currently unknown. METHODS AND RESULTS: Mice lacking PI3Kgamma (PI3Kgamma(-/-)) showed runs of premature ventricular contractions on adrenergic stimulation that could be rescued by a selective beta(2)-adrenergic receptor blocker and developed sustained ventricular tachycardia after transverse aortic constriction. Consistently, fluorescence resonance energy transfer probes revealed abnormal cAMP accumulation after beta(2)-adrenergic receptor activation in PI3Kgamma(-/-) cardiomyocytes that depended on the loss of the scaffold but not of the catalytic activity of PI3Kgamma. Downstream from beta-adrenergic receptors, PI3Kgamma 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 PI3Kgamma-regulated PDEs lowered cAMP and limited protein kinase A-mediated phosphorylation of L-type calcium channel (Ca(v)1.2) and phospholamban. In PI3Kgamma(-/-) cardiomyocytes, Ca(v)1.2 and phospholamban were hyperphosphorylated, leading to increased Ca(2+) spark occurrence and amplitude on adrenergic stimulation. Furthermore, PI3Kgamma(-/-) cardiomyocytes showed spontaneous Ca(2+) release events and developed arrhythmic calcium transients. CONCLUSIONS: PI3Kgamma coordinates the coincident signaling of the major cardiac PDE3 and PDE4 isoforms, thus orchestrating a feedback loop that prevents calcium-dependent ventricular arrhythmia. |
