Integrating Cardiac PIP3 and cAMP Signaling through a PKA Anchoring Function of p110 gamma

Alessia Perino, Alessandra Ghigo, Enrico Ferrero, Fulvio More, 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

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

134 Citations (Web of Science)


Adrenergic stimulation of the heart engages cAMP and phosphoinositide second messenger signaling cascades. Cardiac phosphoinositide 3-kinase p110 gamma participates in these processes by sustaining beta-adrenergic receptor internalization through its catalytic function and by controlling phosphodiesterase 3B (PDE3B) activity via an unknown kinase-independent mechanism. We have discovered that p110 gamma anchors protein kinase A (PKA) through a site in its N-terminal region. Anchored PKA activates PDE3B to enhance cAMP degradation and phosphorylates p110 gamma to inhibit PIP3 production. This provides local feedback control of PIP3 and cAMP signaling events. In congestive heart failure, p110 gamma is upregulated and escapes PKA-mediated inhibition, contributing to a reduction in beta-adrenergic receptor density. Pharmacological inhibition of p110 gamma normalizes beta-adrenergic receptor density and improves contractility in failing hearts.
Original languageEnglish
Pages (from-to)84-95
JournalMolecular Cell
Issue number1
Publication statusPublished - 8 Apr 2011

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