The protein kinase A anchoring protein mAKAP coordinates two integrated cAMP effector pathways

Cyclic adenosine 3′, 5′ monophosphate (cAMP) is a ubiquitous mediator of intracellular signalling events. It principally acts through stimulation of cAMP-dependent protein kinases (PKA)1, 2 but also activates certain ion-channels and guanine nucleotide exchange factors (Epacs)3. Metabolism of cAMP is catalyzed by phosphodiesterases (PDEs)4, 5. A cAMP-responsive signalling complex maintained by the muscle specific A-kinase anchoring protein (mAKAP) that includes PKA, PDE4D3 and Epac1 was identified. These intermolecular interactions facilitate the dissemination of distinct cAMP signals through each effector protein. Anchored PKA stimulates PDE4D3 to reduce local cAMP concentrations whereas an mAKAP-associated ERK5 module suppresses PDE4D3. PDE4D3 also functions as an adapter protein that recruits Epac1, an exchange factor for the small GTPase Rap-1 to enable cAMP-dependent attenuation of ERK5. Pharmacological and molecular manipulation of the mAKAP complex show that anchored ERK5 can induce cardiomyocyte hypertrophy. Thus, two coupled cAMP-dependent feedback loops are coordinated within the context of the mAKAP complex, suggesting that local control of cAMP signalling by AKAPs is more intricate than previously appreciated