Recombinant muscle GYS1 (glycogen synthase 1) and recombinant liver GYS2 were phosphorylated by recombinant AMPK (AMP-activated protein kinase) in a time-dependent manner and to a similar stoichiometry. The phosphorylation site in GYS2 was identified as Ser7, which lies in a favourable consensus for phosphorylation by AMPK. Phosphorylation of GYS1 or GYS2 by AMPK led to enzyme inactivation by decreasing the affinity for both UDP-Glc (UDP-glucose) [assayed in the absence of Glc-6-P (glucose-6-phosphate)] and Glc-6-P (assayed at low UDP-Glc concentrations). Incubation of freshly isolated rat hepatocytes with the pharmacological AMPK activators AICA riboside (5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside) or A769662 led to persistent GYS inactivation and Ser7 phosphorylation, whereas inactivation by glucagon treatment was transient. In hepatocytes from mice harbouring a liver-specific deletion of the AMPK catalytic α1/α2 subunits, GYS2 inactivation by AICA riboside and A769662 was blunted, whereas inactivation by glucagon was unaffected. The results suggest that GYS inactivation by AMPK activators in hepatocytes is due to GYS2 Ser7 phosphorylation.
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Research Article|
March 14 2012
AMP-activated protein kinase phosphorylates and inactivates liver glycogen synthase
Laurent Bultot;
Laurent Bultot
*de Duve Institute, Université catholique de Louvain, Avenue Hippocrate 75, bte B1.74.02, B-1200 Brussels, Belgium
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Bruno Guigas;
Bruno Guigas
†Department of Molecular Cell Biology, Leiden University Medical Center, Postzone S1-P, Postbus 9600, 2300 RC Leiden, The Netherlands
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Alexander Von Wilamowitz-Moellendorff;
Alexander Von Wilamowitz-Moellendorff
‡MRC Protein Phosphorylation Unit, Sir James Black Centre, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, Scotland, U.K.
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Liliane Maisin;
Liliane Maisin
*de Duve Institute, Université catholique de Louvain, Avenue Hippocrate 75, bte B1.74.02, B-1200 Brussels, Belgium
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Didier Vertommen;
Didier Vertommen
*de Duve Institute, Université catholique de Louvain, Avenue Hippocrate 75, bte B1.74.02, B-1200 Brussels, Belgium
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Nusrat Hussain;
Nusrat Hussain
*de Duve Institute, Université catholique de Louvain, Avenue Hippocrate 75, bte B1.74.02, B-1200 Brussels, Belgium
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Monique Beullens;
Monique Beullens
§Laboratory of Biosignaling and Therapeutics, Department of Molecular Cell Biology, University of Leuven, B-3000 Leuven, Belgium
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Joan J. Guinovart;
Joan J. Guinovart
‖Institute for Research in Biomedicine (IRB Barcelona), Baldiri Reixac 10, 08028 Barcelona, Spain
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Marc Foretz;
Marc Foretz
¶INSERM U1016, Institut Cochin, CNRS UMR8104, Université Paris Descartes, Sorbonne Paris Cité, Paris 75014, France
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Benoît Viollet;
Benoît Viollet
¶INSERM U1016, Institut Cochin, CNRS UMR8104, Université Paris Descartes, Sorbonne Paris Cité, Paris 75014, France
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Kei Sakamoto;
Kei Sakamoto
‡MRC Protein Phosphorylation Unit, Sir James Black Centre, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, Scotland, U.K.
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Louis Hue;
Louis Hue
*de Duve Institute, Université catholique de Louvain, Avenue Hippocrate 75, bte B1.74.02, B-1200 Brussels, Belgium
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Mark H. Rider
Mark H. Rider
1
*de Duve Institute, Université catholique de Louvain, Avenue Hippocrate 75, bte B1.74.02, B-1200 Brussels, Belgium
1To whom correspondence should be addressed (email mark.rider@uclouvain.be).
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Publisher: Portland Press Ltd
Received:
November 22 2011
Revision Received:
January 10 2012
Accepted:
January 11 2012
Accepted Manuscript online:
January 11 2012
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2012 Biochemical Society
2012
Biochem J (2012) 443 (1): 193–203.
Article history
Received:
November 22 2011
Revision Received:
January 10 2012
Accepted:
January 11 2012
Accepted Manuscript online:
January 11 2012
Citation
Laurent Bultot, Bruno Guigas, Alexander Von Wilamowitz-Moellendorff, Liliane Maisin, Didier Vertommen, Nusrat Hussain, Monique Beullens, Joan J. Guinovart, Marc Foretz, Benoît Viollet, Kei Sakamoto, Louis Hue, Mark H. Rider; AMP-activated protein kinase phosphorylates and inactivates liver glycogen synthase. Biochem J 1 April 2012; 443 (1): 193–203. doi: https://doi.org/10.1042/BJ20112026
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