mAKAP assembles a protein kinase A/PDE4 phosphodiesterase cAMP signaling module

Spatiotemporal regulation of protein kinase A (PKA) activity involves the m anipulation of compartmentalized cAMP pools. Now we demonstrate that the mu scle-selective A-kinase anchoring protein, mAKAP, maintains a cAMP signalin g module, including PKA and the rolipram-inhibited cAMP-specific phosphodie sterase (PDE4D3) in heart tissues. Functional analyses indicate that tonic PDE4D3 activity reduces the activity of the anchored PKA holoenzyme, wherea s kinase activation stimulates mAKAP-associated phosphodiesterase activity. Disruption of PKA-mAKAP interaction prevents this enhancement of PDE4D3 ac tivity, suggesting that the proximity of both enzymes in the mAKAP signalin g complex forms a negative feedback loop to restore basal cAMP levels.