P99PI3Kgamma protects against catecholamine-induced ventricular arrhythmia through PKA-mediated regulation of distinct phosphodiesterases

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Abstract

Purpose

Phosphoinositide 3-kinase γ (PI3Kγ) signaling downstream β-adrenergic receptors (β-ARs) plays a pivotal role in the regulation of myocardial contractility and maladaptive remodelling. However, the function of PI3Kγ in catecholamine-induced arrhythmia is presently unknown.

Methods and Results

Adrenaline stimulation in mice lacking PI3Kγ triggered runs of premature ventricular contractions thus uncovering PI3Kγ as a crucial mediator of arrhythmia. Consistently, FRET probes revealed abnormal cAMP accumulation following β2-AR activation that depended on PI3Kγ scaffold activity. Downstream β2-ARs, PI3Kγ was found to participate in multi-protein complexes linking PKA to the activation of PDE3A, PDE4A and PDE4B, but not PDE4D. The ensuing negative feedback loop lowered cAMP and limited PKA-mediated phosphorylation of L-type calcium channel and phospholamban, thus preventing arrhythmogenesis.

Conclusions

PI3Kγ protects against catecholamine-induced ventricular arrhythmia by coordinating the coincident signaling of the major cardiac PDE3 and PDE4 isoforms in distinct cellular compartments.

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