title: Regulation of glycogen synthase by glucose and glycogen: a possible role for AMP-activated protein kinase.
abstract: We report here use of human myoblasts in culture to study the relationships between cellular glycogen concentrations and the activities of glycogen synthase (GS) and AMP-activated protein kinase (AMPK). Incubation of cells for 2 h in the absence of glucose led to a 25% decrease in glycogen content and a significant decrease in the fractional activity of GS. This was accompanied by stimulation of both the alpha1 and alpha2 isoforms of AMPK, without significant alterations in the ratios of adenine nucleotides. When glucose was added to glycogen-depleted cells, a rapid and substantial increase in GS activity was accompanied by inactivation of AMPK back to basal values. Inclusion of the glycogen phosphorylase inhibitor, CP-91149, prevented the loss of glycogen during glucose deprivation but not the activation of AMPK. However, in the absence of prior glycogen breakdown, glucose treatment failed to activate GS above control values, indicating the crucial role of glycogen content. Activation of AMPK by either 5-aminoimidazole-4-carboxamide 1-beta-D-ribofuranoside (AICAR) or hydrogen peroxide was also associated with a decrease in the activity ratio of GS. AICAR treatment had no effect on total cellular glycogen content but led to a modest increase in glucose uptake. These data support a role for AMPK in both stimulating glucose uptake and inhibiting GS in intact cells, thus promoting glucose flux through glycolysis.
authors.affiliation: School of Biochemistry and Genetics, Medical School, University of Newcastle, Newcastle upon Tyne, U.K.
authors.forename: Reza
authors.initials: R
authors.lastname: Halse
authors.forename: Lee G D
authors.initials: LG
authors.lastname: Fryer
authors.forename: James G
authors.initials: JG
authors.lastname: McCormack
authors.forename: David
authors.initials: D
authors.lastname: Carling
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Yeaman
mesh_terms: D055372:AMP-Activated Protein Kinases; D000577:Amides / Q000494:pharmacology; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects; D005947:Glucose / Q000172:deficiency / Q000494:pharmacology*; D006003:Glycogen / Q000494:pharmacology*; D024981:Glycogen Phosphorylase / Q000037:antagonists & inhibitors; D006006:Glycogen Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D007527:Isoenzymes / Q000378:metabolism; D009097:Multienzyme Complexes / Q000502:physiology; D032446:Myoblasts / Q000201:enzymology; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D012265:Ribonucleotides / Q000494:pharmacology
chemical_list: D000577:Amides; C110844:CP 91149; D007211:Indoles; D007527:Isoenzymes; D009097:Multienzyme Complexes; D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; D006003:Glycogen; D006861:Hydrogen Peroxide; D024981:Glycogen Phosphorylase; D006006:Glycogen Synthase; C526181:PRKAA2 protein, human; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; C526180:PRKAA1 protein, human; C031143:AICA ribonucleotide; D005947:Glucose