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 I CaL 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 I K,ACh current. In addition, muscarinic‐mediated anti‐adrenergic effect on papillary muscle contractility and I CaL 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.