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mAKAP assembles a protein kinase A/PDE4 phosphodiesterase cAMP signaling module
K L Dodge1, S Khouangsathiene, M S Kapiloff
1Howard Hughes Medical Institute and Vollum Institute, and Department of Pediatrics, Oregon Health Sciences University, Portland, OR 97201-3098, USA.
Abstract:
Spatiotemporal regulation of protein kinase A (PKA) activity involves the manipulation of compartmentalized cAMP pools. Now we demonstrate that the muscle-selective A-kinase anchoring protein, mAKAP, maintains a cAMP signaling module, including PKA and the rolipram-inhibited cAMP-specific phosphodiesterase (PDE4D3) in heart tissues. Functional analyses indicate that tonic PDE4D3 activity reduces the activity of the anchored PKA holoenzyme, whereas kinase activation stimulates mAKAP-associated phosphodiesterase activity. Disruption of PKA- mAKAP interaction prevents this enhancement of PDE4D3 activity, suggesting that the proximity of both enzymes in the mAKAP signaling complex forms a negative feedback loop to restore basal cAMP levels.