| Literature DB >> 21474070 |
Alessia Perino1, Alessandra Ghigo, Enrico Ferrero, Fulvio Morello, Gaetano Santulli, George S Baillie, Federico Damilano, Allan J Dunlop, Catherine Pawson, Romy Walser, Renzo Levi, Fiorella Altruda, Lorenzo Silengo, Lorene K Langeberg, Gitte Neubauer, Stephane Heymans, Giuseppe Lembo, Matthias P Wymann, Reinhard Wetzker, Miles D Houslay, Guido Iaccarino, John D Scott, Emilio Hirsch.
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.Entities:
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Year: 2011 PMID： 21474070 PMCID： PMC3265115 DOI： 10.1016/j.molcel.2011.01.030
Source DB: PubMed Journal: Mol Cell ISSN： 1097-2765 Impact factor: 17.970