title: 5-Aminoimidazole-4-carboxamide 1-beta -D-ribofuranoside (AICAR) stimulates myocardial glycogenolysis by allosteric mechanisms.
abstract: We tested the hypothesis that activation of AMP-activated protein kinase (AMPK) promotes myocardial glycogenolysis by decreasing glycogen synthase (GS) and/or increasing glycogen phosphorylase (GP) activities. Isolated working hearts from halothane-anesthetized male Sprague-Dawley rats perfused in the absence or presence of 0.8 or 1.2 mM 5-aminoimidazole-4-carboxamide 1-beta-d-ribofuranoside (AICAR), an adenosine analog and cell-permeable activator of AMPK, were studied. Glycogen degradation was increased by AICAR, while glycogen synthesis was not affected. AICAR increased myocardial 5-aminoimidazole-4-carboxamide 1-beta-d-ribofuranotide (ZMP), the active intracellular form of AICAR, but did not alter the activity of GS and GP measured in tissue homogenates or the content of glucose-6-phosphate and adenine nucleotides in freeze-clamped tissue. Importantly, the calculated intracellular concentration of ZMP achieved in this study was similar to the K(m) value of ZMP for GP determined in homogenates of myocardial tissue. We conclude that the data are consistent with allosteric activation of GP by ZMP being responsible for the glycogenolysis caused by AICAR in the intact rat heart.
authors.affiliation: McDonald Research Laboratories/The iCAPTUR(4)E Centre, Department of Pathology and Laboratory Medicine, University of British Columbia-St.Paul's Hospital, Vancouver, British Columbia V6Z 1Y6.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Longnus
authors.forename: Richard B
authors.initials: RB
authors.lastname: Wambolt
authors.forename: Hannah L
authors.initials: HL
authors.lastname: Parsons
authors.forename: Roger W
authors.initials: RW
authors.lastname: Brownsey
authors.forename: Michael F
authors.initials: MF
authors.lastname: Allard
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism; D000494:Allosteric Regulation; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D004789:Enzyme Activation / Q000187:drug effects; D006003:Glycogen / Q000378:metabolism*; D024981:Glycogen Phosphorylase / Q000378:metabolism; D006006:Glycogen Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D006321:Heart / Q000187:drug effects*; D008297:Male; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012265:Ribonucleotides / Q000378:metabolism / Q000494:pharmacology*; D013237:Stereoisomerism; D013997:Time Factors
chemical_list: D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; D006003:Glycogen; D024981:Glycogen Phosphorylase; D006006:Glycogen Synthase; D000263:Adenylate Kinase; C031143:AICA ribonucleotide