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

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• 作者：Alessia Perino¹ ; Alessandra Ghigo¹ ; ¹² ; Enrico Ferrero¹ ; ¹² ; Fulvio Morello¹ ; ¹² ; Gaetano Santulli² ; ¹³ ; George  ; S. Baillie³ ; Federico Damilano¹ ; Allan  ; J. Dunlop³ ; Catherine Pawson⁴ ; Romy Walser⁵ ; Renzo Levi⁶ ; Fiorella Altruda¹ ; Lorenzo Silengo¹ ; Lorene  ; K. Langeberg⁴ ; Gitte Neubauer⁷ ; Stephane Heymans⁸ ; Giuseppe Lembo⁹ ; Matthias  ; P. Wymann⁵ ; Reinhard Wetzker¹⁰ ; Miles  ; D. Houslay³ ; Guido Iaccarino¹¹ ; John  ; D. Scott⁴ ; ^{scottjdw@u.washington.edu} ; Emilio Hirsch¹ ; ^{emilio.hirsch@unito.it}
• 刊名：Molecular Cell
• 出版年：2011
• 出版时间：8 April 2011
• 年：2011
• 卷：42
• 期：1
• 页码：84-95
• 全文大小：1559 K

文摘

Summary

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.