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

SummaryAdrenergic 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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► p110γ controls PDE3B activity and cAMP levels by anchoring PKA
► Anchored PKA inhibits p110γ kinase activity in response to adrenergic stimulation
► In heart failure, p110γ escapes PKA inhibition, controlling β-AR internalization
► Inhibition of p110γ in heart failure improves contractility