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Integrating Cardiac PIP3and cAMP Signaling through a PKA Anchoring Function of p110γ

Authors
Publisher
Elsevier Inc.
Publication Date
Volume
42
Issue
1
Identifiers
DOI: 10.1016/j.molcel.2011.01.030
Disciplines
  • Biology

Abstract

Summary 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.

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