AMP-activated protein kinase phosphorylates and inactivates liver glycogen synthase

作者：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^*

来源：Biochemical Journal, 2012, 443(1): 193-203.

DOI：10.1042/BJ20112026

• A769662
• 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICA riboside)
• AMP-activated protein kinase (AMPK)
• glucagon
• glycogen synthase
• hepatocyte

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 Ser(7), 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-beta-D-ribofuranoside) or A769662 led to persistent GYS inactivation and Ser(7) phosphorylation, whereas inactivation by glucagon treatment was transient. In hepatocytes from mice harbouring a liver-specific deletion of the AMPK catalytic alpha 1/alpha 2 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 Ser(7) phosphorylation.

• 出版日期2012-4-1