Integrating cardiac PIP₃ and cAMP signaling through a PKA anchoring function of p110γ

Perino, A. et al. (2011) Integrating cardiac PIP₃ and cAMP signaling through a PKA anchoring function of p110γ. Molecular Cell, 42(1), pp. 84-95.

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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Houslay, Professor Miles and Baillie, Professor George
• Authors: Perino, A., Ghigo, F., 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., Houslay, M.D., Iaccarino, G., Scott, J.D., and Hirsch, E.
• College/School: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
• Journal Name: Molecular Cell
• ISSN: 1097-2765
• ISSN (Online): 1097-4164