title: Integrating cardiac PIP3 and cAMP signaling through a PKA anchoring function of p110γ.
abstract: Adrenergic stimulation of the heart engages cAMP and phosphoinositide second messenger signaling cascades. Cardiac phosphoinositide 3-kinase p110γ participates in these processes by sustaining β-adrenergic receptor internalization through its catalytic function and by controlling phosphodiesterase 3B (PDE3B) activity via an unknown kinase-independent mechanism. We have discovered that p110γ anchors protein kinase A (PKA) through a site in its N-terminal region. Anchored PKA activates PDE3B to enhance cAMP degradation and phosphorylates p110γ to inhibit PIP(3) production. This provides local feedback control of PIP(3) and cAMP signaling events. In congestive heart failure, p110γ is upregulated and escapes PKA-mediated inhibition, contributing to a reduction in β-adrenergic receptor density. Pharmacological inhibition of p110γ normalizes β-adrenergic receptor density and improves contractility in failing hearts.
authors.affiliation: Department of Genetics, Biology and Biochemistry, Molecular Biotechnology Center, University of Torino, Torino 10126, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Perino
authors.forename: Alessandra
authors.initials: A
authors.lastname: Ghigo
authors.forename: Enrico
authors.initials: E
authors.lastname: Ferrero
authors.forename: Fulvio
authors.initials: F
authors.lastname: Morello
authors.forename: Gaetano
authors.initials: G
authors.lastname: Santulli
authors.forename: George S
authors.initials: GS
authors.lastname: Baillie
authors.forename: Federico
authors.initials: F
authors.lastname: Damilano
authors.forename: Allan J
authors.initials: AJ
authors.lastname: Dunlop
authors.forename: Catherine
authors.initials: C
authors.lastname: Pawson
authors.forename: Romy
authors.initials: R
authors.lastname: Walser
authors.forename: Renzo
authors.initials: R
authors.lastname: Levi
authors.forename: Fiorella
authors.initials: F
authors.lastname: Altruda
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Silengo
authors.forename: Lorene K
authors.initials: LK
authors.lastname: Langeberg
authors.forename: Gitte
authors.initials: G
authors.lastname: Neubauer
authors.forename: Stephane
authors.initials: S
authors.lastname: Heymans
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Lembo
authors.forename: Matthias P
authors.initials: MP
authors.lastname: Wymann
authors.forename: Reinhard
authors.initials: R
authors.lastname: Wetzker
authors.forename: Miles D
authors.initials: MD
authors.lastname: Houslay
authors.forename: Guido
authors.initials: G
authors.lastname: Iaccarino
authors.forename: John D
authors.initials: JD
authors.lastname: Scott
authors.forename: Emilio
authors.initials: E
authors.lastname: Hirsch
mesh_terms: D054758:A Kinase Anchor Proteins / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D058544:Class Ib Phosphatidylinositol 3-Kinase / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism*; D054754:Cyclic AMP-Dependent Protein Kinase RIIalpha Subunit / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3 / Q000378:metabolism; D004247:DNA / Q000235:genetics; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006333:Heart Failure / Q000188:drug therapy / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D032383:Myocytes, Cardiac / Q000378:metabolism*; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D025941:Protein Interaction Mapping; D011810:Quinoxalines / Q000494:pharmacology; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D015290:Second Messenger Systems; D017386:Sequence Homology, Amino Acid; D045162:Thiazolidinediones / Q000494:pharmacology
chemical_list: C505144:5-quinoxalin-6-ylmethylenethiazolidine-2,4-dione; D054758:A Kinase Anchor Proteins; D054754:Cyclic AMP-Dependent Protein Kinase RIIalpha Subunit; D004791:Enzyme Inhibitors; C517819:PRKAR2A protein, human; D010446:Peptide Fragments; D018129:Phosphatidylinositol Phosphates; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011810:Quinoxalines; D011943:Receptors, Adrenergic, beta; D045162:Thiazolidinediones; C060974:phosphatidylinositol 3,4,5-triphosphate; D004247:DNA; D000242:Cyclic AMP; D058544:Class Ib Phosphatidylinositol 3-Kinase; C546760:PIK3CG protein, human; C546764:Pik3cg protein, mouse; D017868:Cyclic AMP-Dependent Protein Kinases; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; C517291:PDE3B protein, human