Figure 3.

Regulation of PDE3 and PDE4 by the AKAP function of PI3Kγ. Left panel: Regulation of PI3Kγ and phosphodiesterase activity in healthy conditions. Upon stimulation of β-adrenergic receptors, cAMP production is promoted but simultaneously constrained by the activation of a negative feedback loop involving the scaffold function of PI3Kγ that directly binds the PKA holoenzyme containing the RII regulatory subunit as well as PDE3s and PDE4s. PKA activation leads to the phosphorylation of these phosphodiesterases and the consequent increase in their activity that, in turn, reduces cAMP levels. At the same time, PKA phosphorylates and inhibits PI3Kγ, thus blocking the classical PI3K pathway signalling. Right panel: In the absence of PI3Kγ, PKA is displaced from PDE3 and PDE4 enzymes and is unable to efficiently stimulate their activity. As a consequence, cAMP levels rise and cAMP diffuses to compartments that β-adrenergic receptor-mediated signalling does not usually affect.