AMPK antagonizes hepatic glucagon-stimulated cyclic AMP signalling via phosphorylation-induced activation of cyclic nucleotide phosphodiesterase 4B

M. Johanns; Y. C. Lai; M. F. Hsu; R. Jacobs; D. Vertommen; J. Van Sande; J. E. Dumont; A. Woods; D. Carling; L. Hue; B. Viollet; M. Foretz; M. H. Rider

doi:10.1038/ncomms10856

AMPK antagonizes hepatic glucagon-stimulated cyclic AMP signalling via phosphorylation-induced activation of cyclic nucleotide phosphodiesterase 4B

M. Johanns, Y. C. Lai, M. F. Hsu, R. Jacobs, D. Vertommen, J. Van Sande, J. E. Dumont, A. Woods, D. Carling, L. Hue, B. Viollet, M. Foretz, M. H. Rider^*

^*Corresponding author for this work

Sport, Exercise and Rehabilitation Sciences

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Abstract

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.

Original language	English
Article number	10856
Journal	Nature Communications
Volume	7
DOIs	https://doi.org/10.1038/ncomms10856
Publication status	Published - 8 Mar 2016

Keywords

Cell Signalling
Kinases
Medical research
Phosphorylation

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

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Published as above, final version of record for Johanns, M. et al. AMPK antagonizes hepatic glucagon-stimulated cyclic AMP signalling via phosphorylation-induced activation of cyclic nucleotide phosphodiesterase 4B. Nat. Commun. 7:10856 (2016) available at: doi: 10.1038/ncomms10856. Checked 24/5/18
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Johanns, M., Lai, Y. C., Hsu, M. F., Jacobs, R., Vertommen, D., Van Sande, J., Dumont, J. E., Woods, A., Carling, D., Hue, L., Viollet, B., Foretz, M., & Rider, M. H. (2016). AMPK antagonizes hepatic glucagon-stimulated cyclic AMP signalling via phosphorylation-induced activation of cyclic nucleotide phosphodiesterase 4B. Nature Communications, 7, Article 10856. https://doi.org/10.1038/ncomms10856

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title = "AMPK antagonizes hepatic glucagon-stimulated cyclic AMP signalling via phosphorylation-induced activation of cyclic nucleotide phosphodiesterase 4B",

abstract = "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 Vmax 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.",

keywords = "Cell Signalling, Kinases, Medical research, Phosphorylation",

author = "M. Johanns and Lai, {Y. C.} and Hsu, {M. F.} and R. Jacobs and D. Vertommen and {Van Sande}, J. and Dumont, {J. E.} and A. Woods and D. Carling and L. Hue and B. Viollet and M. Foretz and Rider, {M. H.}",

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Johanns, M, Lai, YC, Hsu, MF, Jacobs, R, Vertommen, D, Van Sande, J, Dumont, JE, Woods, A, Carling, D, Hue, L, Viollet, B, Foretz, M & Rider, MH 2016, 'AMPK antagonizes hepatic glucagon-stimulated cyclic AMP signalling via phosphorylation-induced activation of cyclic nucleotide phosphodiesterase 4B', Nature Communications, vol. 7, 10856. https://doi.org/10.1038/ncomms10856

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AU - Johanns, M.

AU - Lai, Y. C.

AU - Hsu, M. F.

AU - Jacobs, R.

AU - Vertommen, D.

AU - Van Sande, J.

AU - Dumont, J. E.

AU - Woods, A.

AU - Carling, D.

AU - Hue, L.

AU - Viollet, B.

AU - Foretz, M.

AU - Rider, M. H.

PY - 2016/3/8

Y1 - 2016/3/8

N2 - 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 Vmax 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.

AB - 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 Vmax 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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AMPK antagonizes hepatic glucagon-stimulated cyclic AMP signalling via phosphorylation-induced activation of cyclic nucleotide phosphodiesterase 4B

Abstract

Keywords

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