Phosphoinositide 3-kinase γ controls autonomic regulation of the mouse heart through Gi-independent downregulation of cAMP level

Cardiac β-adrenergic and the muscarinic receptors control contractility and heart rate by triggering multiple signaling events involving downstream targets like the phosphoinositide 3-kinase γ (PI3Kγ). We thus investigated whether the lack of PI3Kγ could play a role in the autonomic regulation of the mouse heart. Contractility and ICaL of mutant cardiac preparations appeared increased in basal conditions and after β-adrenergic stimulation. However, basal and β-adrenergic stimulated heart rate were normal. Conversely, muscarinic inhibition of heart rate was reduced without alteration of the Gβγ-dependent stimulation of IK,ACh current. In addition, muscarinic-mediated anti-adrenergic effect on papillary muscle contractility and ICaL was significantly depressed. Consistently, cAMP level of PI3Kγ-null ventricles was always higher than wild-type controls. Thus, PI3Kγ controls the cardiac function by reducing cAMP concentration independently of Gi-mediated signaling.