TY - JOUR
T1 - Phosphoinositide 3-kinase γ protects against catecholamine-induced ventricular arrhythmia through protein kinase A-mediated regulation of distinct phosphodiesterases
AU - Ghigo, Alessandra
AU - Perino, Alessia
AU - Mehel, Hind
AU - Zahradníková, Alexandra
AU - Morello, Fulvio
AU - Leroy, Jérôme
AU - Nikolaev, Viacheslav O.
AU - Damilano, Federico
AU - Cimino, James
AU - De Luca, Elisa
AU - Richter, Wito
AU - Westenbroek, Ruth
AU - Catterall, William A.
AU - Zhang, Jin
AU - Yan, Chen
AU - Conti, Marco
AU - Gomez, Ana Maria
AU - Vandecasteele, Grégoire
AU - Hirsch, Emilio
AU - Fischmeister, Rodolphe
PY - 2012/10/23
Y1 - 2012/10/23
N2 - 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.
AB - 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.
KW - 3=,5=-cyclic-AMP phosphodiesterases
KW - arrhythmias, cardiac
KW - class II phosphatidylinositol 3-kinases
KW - cyclic AMP-dependent protein kinases
KW - receptors, adrenergic beta-2
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U2 - 10.1161/CIRCULATIONAHA.112.114074
DO - 10.1161/CIRCULATIONAHA.112.114074
M3 - Article
C2 - 23008439
AN - SCOPUS:84867881959
SN - 0009-7322
VL - 126
SP - 2073
EP - 2083
JO - Circulation
JF - Circulation
IS - 17
ER -