The α2-5′ AMP-activated protein kinase is a site 2 glycogen synthase kinase in skeletal muscle and is responsive to glucose loading

被引:191
作者
Jorgensen, SB
Nielsen, JN
Birk, JB
Olsen, GS
Viollet, B
Andreelli, F
Schjerling, P
Vaulont, S
Hardie, DG
Hansen, BF
Richter, EA
Wojtaszewski, JFP
机构
[1] Univ Copenhagen, Copenhagen Muscle Res Ctr, Dept Human Physiol, Exercise & Sport Res Inst, DK-2100 Copenhagen, Denmark
[2] Rigshosp, Dept Mol Muscle Biol, DK-2100 Copenhagen, Denmark
[3] Novo Nordisk AS, Diabet Biol, Malov, Denmark
[4] Univ Paris 05, CNRS, INSERM, Dept Genet Dev & Mol Pathol, Paris, France
[5] Univ Dundee, Fac Life Sci, Div Mol Physiol, Dundee, Scotland
关键词
D O I
10.2337/diabetes.53.12.3074
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
The 5'AMP-activated protein kinase (AMPK) is a potential antidiabetic drug target. Here we show that the pharmacological activation of AMPK by 5-aminoimidazole-1-beta-4-carboxamide ribofuranoside (AICAR) leads to inactivation of glycogen synthase (GS) and phosphorylation of GS at Ser 7 (site 2). In muscle of mice with targeted deletion of the alpha2-AMPK gene, phosphorylation of GS site 2 was decreased under basal conditions and unchanged by AICAR treatment. In contrast, in alpha1-AMPK knockout mice, the response to AICAR was normal. Fuel surplus (glucose loading) decreased AMPK activation by AICAR, but the phosphorylation of the downstream targets acetyl-CoA carboxylase-beta and GS was normal. Fractionation studies suggest that this suppression of AMPK activation was not a direct consequence of AMPK association with membranes or glycogen, because AMPK was phosphorylated to a greater extent in response to AICAR in the membrane/glycogen fraction than in the cytosolic fraction. Thus, the downstream action of AMPK in response to AICAR was unaffected by glucose loading, whereas the action of the kinase upstream of AMPK, as judged by AMPK phosphorylation, was decreased. The fact that alpha2-AMPK is a GS kinase that inactivates GS while simultaneously activating glucose transport suggests that a balanced view on the suitability for AMPK as an antidiabetic drug target should be taken.
引用
收藏
页码:3074 / 3081
页数:8
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