Integrating Cardiac PIP3 and cAMP Signaling through a PKA Anchoring Function of p110γ

Alessia Perino, 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. HouslayGuido Iaccarino, John D. Scott, Emilio Hirsch

Research output: Contribution to journalArticle

122 Scopus citations

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 PIP3 production. This provides local feedback control of PIP3 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.

Original languageEnglish (US)
Pages (from-to)84-95
Number of pages12
JournalMolecular Cell
Volume42
Issue number1
DOIs
StatePublished - Apr 8 2011
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Perino, A., Ghigo, A., Ferrero, E., Morello, F., Santulli, G., Baillie, G. S., Damilano, F., Dunlop, A. J., Pawson, C., Walser, R., Levi, R., Altruda, F., Silengo, L., Langeberg, L. K., Neubauer, G., Heymans, S., Lembo, G., Wymann, M. P., Wetzker, R., ... Hirsch, E. (2011). Integrating Cardiac PIP3 and cAMP Signaling through a PKA Anchoring Function of p110γ. Molecular Cell, 42(1), 84-95. https://doi.org/10.1016/j.molcel.2011.01.030