title: Glucagon induces translocation of glucokinase from the cytoplasm to the nucleus of hepatocytes by transfer between 6-phosphofructo 2-kinase/fructose 2,6-bisphosphatase-2 and the glucokinase regulatory protein.
abstract: Glucokinase activity is a major determinant of hepatic glucose metabolism and blood glucose homeostasis. Liver glucokinase activity is regulated acutely by adaptive translocation between the nucleus and the cytoplasm through binding and dissociation from its regulatory protein (GKRP) in the nucleus. Whilst the effect of glucose on this mechanism is well established, the role of hormones in regulating glucokinase location and its interaction with binding proteins remains unsettled. Here we show that treatment of rat hepatocytes with 25mM glucose caused decreased binding of glucokinase to GKRP, translocation from the nucleus and increased binding to 6-phosphofructo 2-kinase/fructose 2,6 bisphosphatase-2 (PFK2/FBPase2) in the cytoplasm. Glucagon caused dissociation of glucokinase from PFK2/FBPase2, concomitant with phosphorylation of PFK2/FBPase2 on Ser-32, uptake of glucokinase into the nucleus and increased interaction with GKRP. Two novel glucagon receptor antagonists attenuated the action of glucagon. This establishes an unequivocal role for hormonal control of glucokinase translocation. Given that glucagon excess contributes to the pathogenesis of diabetes, glucagon may play a role in the defect in glucokinase translocation and activity evident in animal models and human diabetes.
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne, UK.
authors.forename: Kirsty S
authors.initials: KS
authors.lastname: Cullen
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne, UK; Department of Laboratory Medicine, Al-Jouf University, Sakaka, Saudi Arabia.
authors.forename: Ziad H
authors.initials: ZH
authors.lastname: Al-Oanzi
authors.affiliation: The Saad Centre for Pharmacy & Diabetes, School of Biomedical Sciences, University of Ulster, Coleraine, UK.
authors.forename: Finbarr P M
authors.initials: FP
authors.lastname: O'Harte
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne, UK.
authors.forename: Loranne
authors.initials: L
authors.lastname: Agius
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne, UK. Electronic address: Catherine.Arden@ncl.ac.uk.
authors.forename: Catherine
authors.initials: C
authors.lastname: Arden
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D015153:Blotting, Western; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism*; D002478:Cells, Cultured; D003593:Cytoplasm / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D005765:Gastrointestinal Agents / Q000494:pharmacology; D005934:Glucagon / Q000494:pharmacology*; D005941:Glucokinase / Q000235:genetics / Q000378:metabolism*; D006019:Glycolysis / Q000187:drug effects; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007124:Immunoenzyme Techniques; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D025481:Phosphofructokinase-2 / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport / Q000187:drug effects*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D001786:Blood Glucose; D002352:Carrier Proteins; D005765:Gastrointestinal Agents; C499484:Gckr protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D005934:Glucagon; D025481:Phosphofructokinase-2; D005941:Glucokinase
keywords: 6-phosphofructo 2-kinase/fructose 2,6 bisphosphatase-2; Glucagon; Glucokinase; Glucokinase regulatory protein; Hepatocyte