Format

Send to

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

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

Author information

1
Department of Genetics, Biology and Biochemistry, Molecular Biotechnology Center, University of Torino, Torino 10126, Italy.

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.

PMID:
21474070
PMCID:
PMC3265115
DOI:
10.1016/j.molcel.2011.01.030
[Indexed for MEDLINE]
Free PMC Article

Publication types, MeSH terms, Substances, Grant support

Publication types

MeSH terms

Substances

Grant support

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center