Integrating cardiac PIP3 and cAMP signaling through a PKA anchoring function of p110γ

Mol Cell. 2011 Apr 8;42(1):84-95. doi: 10.1016/j.molcel.2011.01.030.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • 5-quinoxalin-6-ylmethylenethiazolidine-2,4-dione
  • A Kinase Anchor Proteins
  • Cyclic AMP-Dependent Protein Kinase RIIalpha Subunit
  • Enzyme Inhibitors
  • PRKAR2A protein, human
  • Peptide Fragments
  • Phosphatidylinositol Phosphates
  • Phosphoinositide-3 Kinase Inhibitors
  • Quinoxalines
  • Receptors, Adrenergic, beta
  • Thiazolidinediones
  • phosphatidylinositol 3,4,5-triphosphate
  • DNA
  • Cyclic AMP
  • Class Ib Phosphatidylinositol 3-Kinase
  • PIK3CG protein, human
  • Pik3cg protein, mouse
  • Cyclic AMP-Dependent Protein Kinases
  • Cyclic Nucleotide Phosphodiesterases, Type 3
  • PDE3B protein, human