The alpha2-5'AMP-activated protein kinase is a site 2 glycogen synthase kinase in skeletal muscle and is responsive to glucose loading.
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.
Jørgensen
Sebastian B
SB
Copenhagen Muscle Research Centre, Department of Human Physiology, Institute of Exercise and Sport Sciences, University of Copenhagen, Copenhagen, Denmark.
Nielsen
Jakob N
JN
Birk
Jesper B
JB
Olsen
Grith Skytte
GS
Viollet
Benoit
B
Andreelli
Fabrizio
F
Schjerling
Peter
P
Vaulont
Sophie
S
Hardie
D Grahame
DG
Hansen
Bo F
BF
Richter
Erik A
EA
Wojtaszewski
Jørgen F P
JF
D000263:Adenylate Kinase / Q000378:metabolism*; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D005947:Glucose / Q000378:metabolism*; D006003:Glycogen / Q000378:metabolism; D006006:Glycogen Synthase / Q000378:metabolism; D038341:Glycogen Synthase Kinases / Q000378:metabolism*; D006614:Hindlimb; D008297:Male; D051379:Mice; D018482:Muscle, Skeletal / Q000201:enzymology*; D010766:Phosphorylation; D051381:Rats; D017208:Rats, Wistar; D012265:Ribonucleotides / Q000378:metabolism / Q000494:pharmacology
D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; D006003:Glycogen; D006006:Glycogen Synthase; D038341:Glycogen Synthase Kinases; D000263:Adenylate Kinase; C031143:AICA ribonucleotide; D005947:Glucose