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

Alessandra Ghigo, Alessia Perino, Hind Mehel, Alexandra Zahradníková, Fulvio Morello, Jérôme Leroy, Viacheslav O. Nikolaev, Federico Damilano, James Cimino, Elisa De Luca, Wito Richter, Ruth Westenbroek, William A. Catterall, Jin Zhang, Chen Yan, Marco Conti, Ana Maria Gomez, Grégoire Vandecasteele, Emilio Hirsch, Rodolphe Fischmeister

Research output: Contribution to journalArticle

Abstract

BACKGROUND-: Phosphoinositide 3-kinase γ (PI3Kγ) signaling engaged by β-adrenergic receptors is pivotal in the regulation of myocardial contractility and remodeling. However, the role of PI3Kγ in catecholamine-induced arrhythmia is currently unknown. METHODS AND RESULTS-: Mice lacking PI3Kγ (PI3Kγ) showed runs of premature ventricular contractions on adrenergic stimulation that could be rescued by a selective β2-adrenergic receptor blocker and developed sustained ventricular tachycardia after transverse aortic constriction. Consistently, fluorescence resonance energy transfer probes revealed abnormal cAMP accumulation after β2-adrenergic receptor activation in PI3Kγ cardiomyocytes that depended on the loss of the scaffold but not of the catalytic activity of PI3Kγ. Downstream from β-adrenergic receptors, PI3Kγ 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 PI3Kγ-regulated PDEs lowered cAMP and limited protein kinase A-mediated phosphorylation of L-type calcium channel (Cav1.2) and phospholamban. In PI3Kγ cardiomyocytes, Cav1.2 and phospholamban were hyperphosphorylated, leading to increased Ca spark occurrence and amplitude on adrenergic stimulation. Furthermore, PI3Kγ cardiomyocytes showed spontaneous Ca release events and developed arrhythmic calcium transients. CONCLUSIONS-: PI3Kγ coordinates the coincident signaling of the major cardiac PDE3 and PDE4 isoforms, thus orchestrating a feedback loop that prevents calcium-dependent ventricular arrhythmia.

Original languageEnglish (US)
Pages (from-to)2073-2083
Number of pages11
JournalCirculation
Volume126
Issue number17
DOIs
StatePublished - Oct 23 2012

Keywords

  • 3=,5=-cyclic-AMP phosphodiesterases
  • arrhythmias, cardiac
  • class II phosphatidylinositol 3-kinases
  • cyclic AMP-dependent protein kinases
  • receptors, adrenergic beta-2

ASJC Scopus subject areas

  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

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    Ghigo, A., Perino, A., Mehel, H., Zahradníková, A., Morello, F., Leroy, J., Nikolaev, V. O., Damilano, F., Cimino, J., De Luca, E., Richter, W., Westenbroek, R., Catterall, W. A., Zhang, J., Yan, C., Conti, M., Gomez, A. M., Vandecasteele, G., Hirsch, E., & Fischmeister, R. (2012). Phosphoinositide 3-kinase γ protects against catecholamine-induced ventricular arrhythmia through protein kinase A-mediated regulation of distinct phosphodiesterases. Circulation, 126(17), 2073-2083. https://doi.org/10.1161/CIRCULATIONAHA.112.114074