Journal
NATURE COMMUNICATIONS
Volume 7, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms10856
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Funding
- Fund for Medical Scientific Research (FNRS, Belgium)
- Interuniversity Attraction Poles (IAP) Programme of the Belgian Science Policy [P7/13]
- Fund for Scientific Research in Industry and Agriculture (FRIA)
- Interuniversity Poles of Attraction Belgian Science Policy [P7/13]
- Directorate General Higher Education and Scientific Research French Community of Belgium
- Fonds de la Recherche Scientifique (FNRS, Belgium) [3.4518.11]
- Region Ile-de-France (CORDDIM)
- Societe Francophone du Diabete (SFD)
- MRC [MC_U120027537] Funding Source: UKRI
- Medical Research Council [MC_U120027537] Funding Source: researchfish
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Biguanides such as metformin have previously been shown to antagonize hepatic glucagon-stimulated cyclic AMP (cAMP) signalling independently of AMP-activated protein kinase (AMPK) via direct inhibition of adenylate cyclase by AMP. Here we show that incubation of hepatocytes with the small-molecule AMPK activator 991 decreases glucagon-stimulated cAMP accumulation, cAMP-dependent protein kinase (PKA) activity and downstream PKA target phosphorylation. Moreover, incubation of hepatocytes with 991 increases the V-max of cyclic nucleotide phosphodiesterase 4B (PDE4B) without affecting intracellular adenine nucleotide concentrations. The effects of 991 to decrease glucagon-stimulated cAMP concentrations and activate PDE4B are lost in hepatocytes deleted for both catalytic subunits of AMPK. PDE4B is phosphorylated by AMPK at three sites, and by site-directed mutagenesis, Ser304 phosphorylation is important for activation. In conclusion, we provide a new mechanism by which AMPK antagonizes hepatic glucagon signalling via phosphorylation-induced PDE4B activation.
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