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

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 β(2)-adrenergic receptor blocker and developed sustained ventricular tachycardia after transverse aortic constriction. Consistently, fluorescence resonance energy transfer probes revealed abnormal cAMP accumulation after β(2)-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 (Ca(v)1.2) and phospholamban. In PI3Kγ(-/-) cardiomyocytes, Ca(v)1.2 and phospholamban were hyperphosphorylated, leading to increased Ca(2+) spark occurrence and amplitude on adrenergic stimulation. Furthermore, PI3Kγ(-/-) cardiomyocytes showed spontaneous Ca(2+) 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.

• Authors: Alessandra Ghigo, Alessia Perino, Hind Mehel, Alexandra Zahradníková Jr, 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
• Journal: Circulation (Circulation) Vol. 126 Issue 17 Pg. 2073-83 (Oct 23 2012) ISSN: 1524-4539 [Electronic] United States
• PMID: 23008439 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Catecholamines
• Isoenzymes
• Class Ib Phosphatidylinositol 3-Kinase
• Pik3cg protein, mouse
• Cyclic AMP-Dependent Protein Kinases
• Cyclic Nucleotide Phosphodiesterases, Type 3
• Cyclic Nucleotide Phosphodiesterases, Type 4
• PDE3A protein, human
• PDE4A protein, human
• PDE4B protein, human

Topics

• Animals
• Animals, Newborn
• Biofeedback, Psychology (physiology)
• Calcium Signaling (genetics)
• Catecholamines (toxicity)
• Class Ib Phosphatidylinositol 3-Kinase (deficiency, genetics, physiology)
• Cyclic AMP-Dependent Protein Kinases (physiology)
• Cyclic Nucleotide Phosphodiesterases, Type 3 (metabolism)
• Cyclic Nucleotide Phosphodiesterases, Type 4 (metabolism)
• Gene Knock-In Techniques
• Isoenzymes (metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mice, Transgenic
• Myocytes, Cardiac (enzymology)
• Tachycardia, Ventricular (enzymology, prevention & control)