AMP-activated protein kinase phosphorylates and inactivates liver glycogen synthase
Bultot, Laurent × Guigas, Bruno Von Wilamowitz-Moellendorff, Alexander Maisin, Liliane Vertommen, Didier Hussain, Nusrat Beullens, Monique Guinovart, Joan J Foretz, Marc Viollet, Benoit Sakamoto, Kei Hue, Louis Rider, Mark H #
Published by Portland Press on behalf of the Biochemical Society
Biochemical Journal vol:443 pages:193-203
Recombinant muscle glycogen synthase-1 (GYS1) and recombinant liver glycogen synthase-2 (GYS2) were phosphorylated by recombinant AMP-activated protein kinase (AMPK) in a time-dependent manner and to a similar stoichiometry. The phosphorylation site in GYS2 was identified as Ser7, which lies in a favorable consensus for phosphorylation by AMPK. Phosphorylation of GYS1 or GYS2 by AMPK led to enzyme inactivation by decreasing the affinity for both UDP-Glc (assayed in the absence of Glc-6-P) and Glc-6-P (assayed at low UDP-Glc concentrations). Incubation of freshly isolated rat hepatocytes with pharmacological AMPK activators 5-aminoimidazole-4-carboxamide-1-b-D-ribofuranoside (AICA riboside) or A769662 led to persistent GYS inactivation and Ser7 phosphorylation, whereas inactivation by glucagon treatment was transient. In hepatocytes from mice harboring a liver-specific deletion of the AMPK catalytic a1/a2 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.