Adrenergic stimulation of the heart engages cAMP and phosphoinositide second messenger signaling cascades. Cardiac phosphoinositide 3-kinase p110 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 p110 anchors protein kinase A (PKA) through a site in its N-terminal region. Anchored PKA activates PDE3B to enhance cAMP degradation and phosphorylates p110 to inhibit PIP3 production. This provides local feedback control of PIP3 and cAMP signaling events. In congestive heart failure, p110 is upregulated and escapes PKA-mediated inhibition, contributing to a reduction in β-adrenergic receptor density. Pharmacological inhibition of p110 normalizes β-adrenergic receptor density and improves contractility in failing hearts.

Integrating Cardiac PIP(3) and cAMP Signaling through a PKA Anchoring Function of p110γ.

PERINO, Alessia;GHIGO, Alessandra;FERRERO, Enrico;MORELLO, Fulvio;DAMILANO, Federico;LEVI, Renzo;ALTRUDA, Fiorella;SILENGO, Lorenzo;HIRSCH, Emilio
2011-01-01

Abstract

Adrenergic stimulation of the heart engages cAMP and phosphoinositide second messenger signaling cascades. Cardiac phosphoinositide 3-kinase p110 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 p110 anchors protein kinase A (PKA) through a site in its N-terminal region. Anchored PKA activates PDE3B to enhance cAMP degradation and phosphorylates p110 to inhibit PIP3 production. This provides local feedback control of PIP3 and cAMP signaling events. In congestive heart failure, p110 is upregulated and escapes PKA-mediated inhibition, contributing to a reduction in β-adrenergic receptor density. Pharmacological inhibition of p110 normalizes β-adrenergic receptor density and improves contractility in failing hearts.
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http://www.cell.com/molecular-cell/abstract/S1097-2765(11)00164-X?switch=standard
heart failure cAMP PKA PI3K signal transduction
Perino A; Ghigo A; Ferrero E; Morello F; Santulli G; Baillie GS; Damilano F; Dunlop AJ; Pawson C; Walser R; Levi R; Altruda F; Silengo L; Langeberg LK; Neubauer G; Heymans S; Lembo G; Wymann MP; Wetzker R; Houslay MD; Iaccarino G; Scott JD; Hirsch E
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/87366
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