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. Houslay; Guido Iaccarino; John D. Scott; Emilio Hirsch

doi:10.1016/j.molcel.2011.01.030

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 journal › Article › Academic › peer-review

134 Citations (Web of Science)

Abstract

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 language	English
Pages (from-to)	84-95
Journal	Molecular Cell
Volume	42
Issue number	1
DOIs	https://doi.org/10.1016/j.molcel.2011.01.030
Publication status	Published - 8 Apr 2011

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10.1016/j.molcel.2011.01.030

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Perino, A., Ghigo, A., Ferrero, E., More, 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 p110 gamma. Molecular Cell, 42(1), 84-95. https://doi.org/10.1016/j.molcel.2011.01.030

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title = "Integrating Cardiac PIP3 and cAMP Signaling through a PKA Anchoring Function of p110 gamma",

abstract = "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.",

author = "Alessia Perino and Alessandra Ghigo and Enrico Ferrero and Fulvio More and Gaetano Santulli and Baillie, {George S.} and Federico Damilano and Dunlop, {Allan J.} and Catherine Pawson and Romy Walser and Renzo Levi and Fiorella Altruda and Lorenzo Silengo and Langeberg, {Lorene K.} and Gitte Neubauer and Stephane Heymans and Giuseppe Lembo and Wymann, {Matthias P.} and Reinhard Wetzker and Houslay, {Miles D.} and Guido Iaccarino and Scott, {John D.} and Emilio Hirsch",

year = "2011",

month = apr,

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doi = "10.1016/j.molcel.2011.01.030",

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Perino, A, Ghigo, A, Ferrero, E, More, 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 2011, 'Integrating Cardiac PIP3 and cAMP Signaling through a PKA Anchoring Function of p110 gamma', Molecular Cell, vol. 42, no. 1, pp. 84-95. https://doi.org/10.1016/j.molcel.2011.01.030

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AU - Perino, Alessia

AU - Ghigo, Alessandra

AU - Ferrero, Enrico

AU - More, Fulvio

AU - Santulli, Gaetano

AU - Baillie, George S.

AU - Damilano, Federico

AU - Dunlop, Allan J.

AU - Pawson, Catherine

AU - Walser, Romy

AU - Levi, Renzo

AU - Altruda, Fiorella

AU - Silengo, Lorenzo

AU - Langeberg, Lorene K.

AU - Neubauer, Gitte

AU - Heymans, Stephane

AU - Lembo, Giuseppe

AU - Wymann, Matthias P.

AU - Wetzker, Reinhard

AU - Houslay, Miles D.

AU - Iaccarino, Guido

AU - Scott, John D.

AU - Hirsch, Emilio

PY - 2011/4/8

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N2 - 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.

AB - 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.

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