Fig. 6. mAKAP maintains an anchored PKA/PDE4D3 negative feedback loop. The cartoon depicts the proposed feedback inhibition of anchored PKA by mAKAP-associated PDE4DE3 activity. (A) Under basal conditions, the PKA holoenzyme is dormant and the localized constitutively active PDE maintains cAMP concentrations below an activation threshold for the kinase. (B) Upon hormonal stimulation, the increased flow of second messenger overcomes the rate of PDE-mediated cAMP degradation. This promotes release of the PKA catalytic (C) subunit. (C) PKA phosphorylation of mAKAP-associated PDE4D3 stimulates PDE activity, thereby driving cAMP levels back to basal. This favors reformation of the PKA holoenzyme.