Integrating Cardiac PIP3 and cAMP Signaling through a PKA Anchoring Function of p110γ

Alessia Perino; Alessandra Ghigo; Enrico Ferrero; Fulvio Morello; 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 p110γ

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

Research output: Contribution to journal › Article › peer-review

147 Scopus citations

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.

Original language	English (US)
Pages (from-to)	84-95
Number of pages	12
Journal	Molecular Cell
Volume	42
Issue number	1
DOIs	https://doi.org/10.1016/j.molcel.2011.01.030
State	Published - Apr 8 2011
Externally published	Yes

ASJC Scopus subject areas

Molecular Biology
Cell Biology

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10.1016/j.molcel.2011.01.030

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Perino, A., Ghigo, A., 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., ... Hirsch, E. (2011). Integrating Cardiac PIP₃ and cAMP Signaling through a PKA Anchoring Function of p110γ. Molecular Cell, 42(1), 84-95. https://doi.org/10.1016/j.molcel.2011.01.030

Integrating Cardiac PIP₃ and cAMP Signaling through a PKA Anchoring Function of p110γ. / Perino, Alessia; Ghigo, Alessandra; Ferrero, Enrico; Morello, Fulvio; Santulli, Gaetano; Baillie, George S.; Damilano, Federico; Dunlop, Allan J.; Pawson, Catherine; Walser, Romy; Levi, Renzo; Altruda, Fiorella; Silengo, Lorenzo; Langeberg, Lorene K.; Neubauer, Gitte; Heymans, Stephane; Lembo, Giuseppe; Wymann, Matthias P.; Wetzker, Reinhard; Houslay, Miles D.; Iaccarino, Guido; Scott, John D.; Hirsch, Emilio.

In: Molecular Cell, Vol. 42, No. 1, 08.04.2011, p. 84-95.

Research output: Contribution to journal › Article › peer-review

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 2011, 'Integrating Cardiac PIP₃ and cAMP Signaling through a PKA Anchoring Function of p110γ', Molecular Cell, vol. 42, no. 1, pp. 84-95. https://doi.org/10.1016/j.molcel.2011.01.030

Perino, Alessia ; Ghigo, Alessandra ; Ferrero, Enrico ; Morello, Fulvio ; Santulli, Gaetano ; Baillie, George S. ; Damilano, Federico ; Dunlop, Allan J. ; Pawson, Catherine ; Walser, Romy ; Levi, Renzo ; Altruda, Fiorella ; Silengo, Lorenzo ; Langeberg, Lorene K. ; Neubauer, Gitte ; Heymans, Stephane ; Lembo, Giuseppe ; Wymann, Matthias P. ; Wetzker, Reinhard ; Houslay, Miles D. ; Iaccarino, Guido ; Scott, John D. ; Hirsch, Emilio. / Integrating Cardiac PIP₃ and cAMP Signaling through a PKA Anchoring Function of p110γ. In: Molecular Cell. 2011 ; Vol. 42, No. 1. pp. 84-95.

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title = "Integrating Cardiac PIP3 and cAMP Signaling through a PKA Anchoring Function of p110γ",

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.",

author = "Alessia Perino and Alessandra Ghigo and Enrico Ferrero and Fulvio Morello 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",

note = "Funding Information: We would like to thank M. Zaccolo (University of Glasgow), J. Beavo (University of Washington), J. Hamm (University of Torino), and all the members of E.H.'s lab. This work was supported by grants from Fondation Leducq (06CDV02 to E.H., J.D.S., G.S.B., and M.D.H.), the European Union Sixth Framework Program EuGeneHeart (E.H.), Telethon (E.H.), Regione Piemonte (E.H.), University of Torino (E.H.), AIRC (E.H.), NIH (grant HL08836 to J.D.S.), and Medical Research Council UK (G0600675 to G.S.B. and M.D.H.). ",

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AU - Ghigo, Alessandra

AU - Ferrero, Enrico

AU - Morello, 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

N1 - Funding Information: We would like to thank M. Zaccolo (University of Glasgow), J. Beavo (University of Washington), J. Hamm (University of Torino), and all the members of E.H.'s lab. This work was supported by grants from Fondation Leducq (06CDV02 to E.H., J.D.S., G.S.B., and M.D.H.), the European Union Sixth Framework Program EuGeneHeart (E.H.), Telethon (E.H.), Regione Piemonte (E.H.), University of Torino (E.H.), AIRC (E.H.), NIH (grant HL08836 to J.D.S.), and Medical Research Council UK (G0600675 to G.S.B. and M.D.H.).

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N2 - 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.

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Integrating Cardiac PIP₃ and cAMP Signaling through a PKA Anchoring Function of p110γ

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