Lithium ions increase hepatic glycogen synthase stability through a proteasome-related mechanism.
Incubation of rat hepatocytes with LiCl resulted in an overall increase in the activity ratio of glycogen synthase (GS), concomitantly with a decrease in active GS kinase-3 levels. GS total activity was also increased in a dose- and time-dependent manner. This latter effect correlated with the amount of immunoreactive enzyme determined by immunoblotting. Cycloheximide and actinomycin-D did not modify LiCl action on GS activity. Lithium ions did not induce any changes in GS mRNA levels. Furthermore, the increase in the total amount of GS induced by LiCl was further augmented after addition of a specific, calpain and proteasome inhibitor. Our results indicate that LiCl increases hepatocyte GS activity through increasing both the activation state of the enzyme and its cellular content. This latter increase is mediated through a modification of the proteasome-regulated proteolytic pathway of the enzyme.
Fernández-Novell
Josep M
JM
Departament de Bioquímica i Biologia Molecular, Universitat de Barcelona, Avgda. Diagonal 645, Edifici nou planta-1, E-08028 Barcelona, Spain. jmfernandeznovell@ub.edu
Rodríguez-Gil
Joan E
JE
Barberà
Albert
A
Guinovart
Joan J
JJ
D000818:Animals; D002154:Calpain / Q000037:antagonists & inhibitors; D002414:Cations, Monovalent; D002478:Cells, Cultured; D003513:Cycloheximide / Q000494:pharmacology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D003609:Dactinomycin / Q000494:pharmacology; D004789:Enzyme Activation; D006006:Glycogen Synthase / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects; D007976:Leupeptins / Q000494:pharmacology; D018021:Lithium Chloride / Q000494:pharmacology*; D008112:Liver Glycogen / Q000378:metabolism; D008297:Male; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D002414:Cations, Monovalent; D015853:Cysteine Proteinase Inhibitors; D007976:Leupeptins; D008112:Liver Glycogen; D061988:Proteasome Inhibitors; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; C063261:acetylleucyl-leucyl-norleucinal; D003609:Dactinomycin; D003513:Cycloheximide; D006006:Glycogen Synthase; D038362:Glycogen Synthase Kinase 3; D002154:Calpain; D046988:Proteasome Endopeptidase Complex; D018021:Lithium Chloride