title: 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.
  
  
  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.affiliation: Molecular Biotechnology Center, University of Torino, Via Nizza 52, 10126 Torino, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Ghigo
authors.forename: Alessia
authors.initials: A
authors.lastname: Perino
authors.forename: Hind
authors.initials: H
authors.lastname: Mehel
authors.forename: Alexandra
authors.initials: A
authors.lastname: Zahradníková
authors.forename: Fulvio
authors.initials: F
authors.lastname: Morello
authors.forename: Jérôme
authors.initials: J
authors.lastname: Leroy
authors.forename: Viacheslav O
authors.initials: VO
authors.lastname: Nikolaev
authors.forename: Federico
authors.initials: F
authors.lastname: Damilano
authors.forename: James
authors.initials: J
authors.lastname: Cimino
authors.forename: Elisa
authors.initials: E
authors.lastname: De Luca
authors.forename: Wito
authors.initials: W
authors.lastname: Richter
authors.forename: Ruth
authors.initials: R
authors.lastname: Westenbroek
authors.forename: William A
authors.initials: WA
authors.lastname: Catterall
authors.forename: Jin
authors.initials: J
authors.lastname: Zhang
authors.forename: Chen
authors.initials: C
authors.lastname: Yan
authors.forename: Marco
authors.initials: M
authors.lastname: Conti
authors.forename: Ana Maria
authors.initials: AM
authors.lastname: Gomez
authors.forename: Grégoire
authors.initials: G
authors.lastname: Vandecasteele
authors.forename: Emilio
authors.initials: E
authors.lastname: Hirsch
authors.forename: Rodolphe
authors.initials: R
authors.lastname: Fischmeister
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001676:Biofeedback, Psychology / Q000502:physiology; D020013:Calcium Signaling / Q000235:genetics; D002395:Catecholamines / Q000633:toxicity*; D058544:Class Ib Phosphatidylinositol 3-Kinase / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology*; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3 / Q000378:metabolism*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism*; D055879:Gene Knock-In Techniques; D007527:Isoenzymes / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000201:enzymology; D017180:Tachycardia, Ventricular / Q000201:enzymology* / Q000517:prevention & control*
chemical_list: D002395:Catecholamines; D007527:Isoenzymes; D058544:Class Ib Phosphatidylinositol 3-Kinase; C546764:Pik3cg protein, mouse; D017868:Cyclic AMP-Dependent Protein Kinases; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C517287:PDE3A protein, human; C517355:PDE4A protein, human; C517360:PDE4B protein, human