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http://purl.uniprot.org/citations/23008439http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/23008439http://www.w3.org/2000/01/rdf-schema#comment"

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."xsd:string
http://purl.uniprot.org/citations/23008439http://purl.org/dc/terms/identifier"doi:10.1161/circulationaha.112.114074"xsd:string
http://purl.uniprot.org/citations/23008439http://purl.uniprot.org/core/author"Hirsch E."xsd:string
http://purl.uniprot.org/citations/23008439http://purl.uniprot.org/core/author"Zhang J."xsd:string
http://purl.uniprot.org/citations/23008439http://purl.uniprot.org/core/author"Fischmeister R."xsd:string
http://purl.uniprot.org/citations/23008439http://purl.uniprot.org/core/author"Yan C."xsd:string
http://purl.uniprot.org/citations/23008439http://purl.uniprot.org/core/author"Richter W."xsd:string
http://purl.uniprot.org/citations/23008439http://purl.uniprot.org/core/author"Gomez A.M."xsd:string
http://purl.uniprot.org/citations/23008439http://purl.uniprot.org/core/author"Conti M."xsd:string
http://purl.uniprot.org/citations/23008439http://purl.uniprot.org/core/author"Catterall W.A."xsd:string
http://purl.uniprot.org/citations/23008439http://purl.uniprot.org/core/author"Leroy J."xsd:string
http://purl.uniprot.org/citations/23008439http://purl.uniprot.org/core/author"Perino A."xsd:string
http://purl.uniprot.org/citations/23008439http://purl.uniprot.org/core/author"De Luca E."xsd:string
http://purl.uniprot.org/citations/23008439http://purl.uniprot.org/core/author"Nikolaev V.O."xsd:string
http://purl.uniprot.org/citations/23008439http://purl.uniprot.org/core/author"Damilano F."xsd:string
http://purl.uniprot.org/citations/23008439http://purl.uniprot.org/core/author"Ghigo A."xsd:string
http://purl.uniprot.org/citations/23008439http://purl.uniprot.org/core/author"Morello F."xsd:string
http://purl.uniprot.org/citations/23008439http://purl.uniprot.org/core/author"Vandecasteele G."xsd:string
http://purl.uniprot.org/citations/23008439http://purl.uniprot.org/core/author"Westenbroek R."xsd:string
http://purl.uniprot.org/citations/23008439http://purl.uniprot.org/core/author"Zahradnikova A. Jr."xsd:string
http://purl.uniprot.org/citations/23008439http://purl.uniprot.org/core/author"Cimino J."xsd:string
http://purl.uniprot.org/citations/23008439http://purl.uniprot.org/core/author"Mehel H."xsd:string
http://purl.uniprot.org/citations/23008439http://purl.uniprot.org/core/date"2012"xsd:gYear
http://purl.uniprot.org/citations/23008439http://purl.uniprot.org/core/name"Circulation"xsd:string
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