Phosphoinositide 3-kinase gamma 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 ICaL 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 Gbetagamma-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 PI3Kgamma-null ventricles was always higher than wild-type controls. Thus, PI3Kgamma controls the cardiac function by reducing cAMP concentration independently of Gi-mediated signaling.
Alloatti
Giuseppe
G
Dipartimento di Biologia Animale e dell'Uomo, Università di Torino, 10123 Torino, Italy.
Marcantoni
Andrea
A
Levi
Renzo
R
Gallo
Maria Pia
MP
Del Sorbo
Lorenzo
L
Patrucco
Enrico
E
Barberis
Laura
L
Malan
Daniela
D
Azzolino
Ornella
O
Wymann
Matthias
M
Hirsch
Emilio
E
Montrucchio
Giuseppe
G
D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D058544:Class Ib Phosphatidylinositol 3-Kinase; D000242:Cyclic AMP / Q000032:analysis / Q000378:metabolism*; D015536:Down-Regulation; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism; D006339:Heart Rate / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000235:genetics / Q000502:physiology*; D007545:Isoproterenol / Q000494:pharmacology; D051379:Mice; D008817:Mice, Mutant Strains; D018727:Muscarinic Antagonists / Q000494:pharmacology*; D009200:Myocardial Contraction / Q000235:genetics / Q000502:physiology*; D009206:Myocardium / Q000737:chemistry / Q000201:enzymology*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000502:physiology*; D024661:Potassium Channels, Inwardly Rectifying / Q000502:physiology; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000502:physiology; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000502:physiology
D000318:Adrenergic beta-Agonists; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D007527:Isoenzymes; D018727:Muscarinic Antagonists; D024661:Potassium Channels, Inwardly Rectifying; D011943:Receptors, Adrenergic, beta; D011976:Receptors, Muscarinic; D002217:Carbachol; D000242:Cyclic AMP; D019869:Phosphatidylinositol 3-Kinases; D058544:Class Ib Phosphatidylinositol 3-Kinase; C546764:Pik3cg protein, mouse; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D007545:Isoproterenol