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

Cardiac beta-adrenergic and the muscarinic receptors control contractility and heart rate by triggering multiple signaling events involving downstream targets like the phosphoinositide 3-kinase gamma (PI3Kgamma). We thus investigated whether the lack of PI3Kgamma 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 beta-adrenergic stimulation. However, basal and beta-adrenergic stimulated heart rate were normal. Conversely, muscarinic inhibition of heart rate was reduced without alteration of the G(betagamma)-dependent stimulation of I-K,I-ACh current. In addition, muscarinic-mediated anti-adrenergic effect on papillary muscle contractility and I-CaL was significantly depressed. Consistently, cAMP level of PI3Kgamma-null ventricles was always higher than wild-type controls. Thus, PI3Kgamma controls the cardiac function by reducing cAMP concentration independently of G(i)-mediated signaling. (C) 2004 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.