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

Authors:
Alessia Perino
Alessia Perino
Molecular Biotechnology Center
Torino | Italy
Alessandra Ghigo
Alessandra Ghigo
Molecular Biotechnology Center
Italy
Enrico Ferrero
Enrico Ferrero
University of Trieste
Italy
Fulvio Morello
Fulvio Morello
University of Torino
Italy
Gaetano Santulli
Gaetano Santulli
Federico II University of Naples
Italy
George S Baillie
George S Baillie
Institute of Cardiovascular and Medical Sciences
ตำบลตลาดบัวขวัญ | Thailand
Federico Damilano
Federico Damilano
Molecular Biotechnology Center
Sheffield | United Kingdom
Allan J Dunlop
Allan J Dunlop
University of Glasgow
United Kingdom

Mol Cell 2011 Apr;42(1):84-95

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

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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Source
http://dx.doi.org/10.1016/j.molcel.2011.01.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3265115PMC
April 2011
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56 Citations
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