as-605240 and Heart-Failure

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.

Topics: A Kinase Anchor Proteins; Amino Acid Sequence; Animals; Base Sequence; Cell Line; Class Ib Phosphatidylinositol 3-Kinase; Cyclic AMP; Cyclic AMP-Dependent Protein Kinase RIIalpha Subunit; Cyclic AMP-Dependent Protein Kinases; Cyclic Nucleotide Phosphodiesterases, Type 3; DNA; Enzyme Activation; Enzyme Inhibitors; Heart Failure; Humans; Mice; Mice, Inbred C57BL; Mice, Knockout; Molecular Sequence Data; Myocytes, Cardiac; Peptide Fragments; Phosphatidylinositol Phosphates; Phosphoinositide-3 Kinase Inhibitors; Phosphorylation; Protein Interaction Mapping; Quinoxalines; Receptors, Adrenergic, beta; Second Messenger Systems; Sequence Homology, Amino Acid; Thiazolidinediones