Dataset Information

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

ABSTRACT: Phosphoinositide 3-kinase ? (PI3K?) signaling engaged by ?-adrenergic receptors is pivotal in the regulation of myocardial contractility and remodeling. However, the role of PI3K? in catecholamine-induced arrhythmia is currently unknown.Mice lacking PI3K? (PI3K?(-/-)) showed runs of premature ventricular contractions on adrenergic stimulation that could be rescued by a selective ?(2)-adrenergic receptor blocker and developed sustained ventricular tachycardia after transverse aortic constriction. Consistently, fluorescence resonance energy transfer probes revealed abnormal cAMP accumulation after ?(2)-adrenergic receptor activation in PI3K?(-/-) cardiomyocytes that depended on the loss of the scaffold but not of the catalytic activity of PI3K?. Downstream from ?-adrenergic receptors, PI3K? 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 PI3K?-regulated PDEs lowered cAMP and limited protein kinase A-mediated phosphorylation of L-type calcium channel (Ca(v)1.2) and phospholamban. In PI3K?(-/-) cardiomyocytes, Ca(v)1.2 and phospholamban were hyperphosphorylated, leading to increased Ca(2+) spark occurrence and amplitude on adrenergic stimulation. Furthermore, PI3K?(-/-) cardiomyocytes showed spontaneous Ca(2+) release events and developed arrhythmic calcium transients.PI3K? coordinates the coincident signaling of the major cardiac PDE3 and PDE4 isoforms, thus orchestrating a feedback loop that prevents calcium-dependent ventricular arrhythmia.

SUBMITTER: Ghigo A

PROVIDER: S-EPMC3913165 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Ghigo Alessandra A Perino Alessia A Mehel Hind H Zahradníková Alexandra A Morello Fulvio F Leroy Jérôme J Nikolaev Viacheslav O VO Damilano Federico F Cimino James J De Luca Elisa E Richter Wito W Westenbroek Ruth R Catterall William A WA Zhang Jin J Yan Chen C Conti Marco M Gomez Ana Maria AM Vandecasteele Grégoire G Hirsch Emilio E Fischmeister Rodolphe R

Circulation 20120924 17

<h4>Background</h4>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.<h4>Methods and results</h4>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 ta ...[more]

PMID: 23008439

Similar Datasets

Project description:RATIONALE:Hypokalemia occurs in up to 20% of hospitalized patients and is associated with increased incidence of ventricular and atrial fibrillation. It is unclear whether these differing types of arrhythmia result from direct and perhaps distinct effects of hypokalemia on cardiomyocytes. OBJECTIVE:To investigate proarrhythmic mechanisms of hypokalemia in ventricular and atrial myocytes. METHODS AND RESULTS:Experiments were performed in isolated rat myocytes exposed to simulated hypokalemia conditions (reduction of extracellular [K+] from 5.0 to 2.7 mmol/L) and supported by mathematical modeling studies. Ventricular cells subjected to hypokalemia exhibited Ca2+ overload and increased generation of both spontaneous Ca2+ waves and delayed afterdepolarizations. However, similar Ca2+-dependent spontaneous activity during hypokalemia was only observed in a minority of atrial cells that were observed to contain t-tubules. This effect was attributed to close functional pairing of the Na+-K+ ATPase and Na+-Ca2+ exchanger proteins within these structures, as reduction in Na+ pump activity locally inhibited Ca2+ extrusion. Ventricular myocytes and tubulated atrial myocytes additionally exhibited early afterdepolarizations during hypokalemia, associated with Ca2+ overload. However, early afterdepolarizations also occurred in untubulated atrial cells, despite Ca2+ quiescence. These phase-3 early afterdepolarizations were rather linked to reactivation of nonequilibrium Na+ current, as they were rapidly blocked by tetrodotoxin. Na+ current-driven early afterdepolarizations in untubulated atrial cells were enabled by membrane hyperpolarization during hypokalemia and short action potential configurations. Brief action potentials were in turn maintained by ultra-rapid K+ current (IKur); a current which was found to be absent in tubulated atrial myocytes and ventricular myocytes. CONCLUSIONS:Distinct mechanisms underlie hypokalemia-induced arrhythmia in the ventricle and atrium but also vary between atrial myocytes depending on subcellular structure and electrophysiology.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets