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. © 2011 Elsevier Inc.
Integrating Cardiac PIP3 and cAMP Signaling through a PKA Anchoring Function of p110γ / Perino, A.; Ghigo, A.; Ferrero, E.; Morello, F.; Santulli, G.; Baillie, G.; Damilano, F.; Dunlop, A.; Pawson, C.; Walser, R.; Levi, R.; Altruda, F.; Silengo, L.; Langeberg, L.; Neubauer, G.; Heymans, S.; Lembo, G.; Wymann, M.; Wetzker, R.; Houslay, M.; Iaccarino, G.; Scott, J.; Hirsch, E.. - In: MOLECULAR CELL. - ISSN 1097-2765. - 42:1(2011), pp. 84-95. [10.1016/j.molcel.2011.01.030]
Integrating Cardiac PIP3 and cAMP Signaling through a PKA Anchoring Function of p110γ
Santulli G.;Altruda F.;Heymans S.;Lembo G.;Iaccarino G.;Hirsch E.
2011
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. © 2011 Elsevier Inc.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
