The mood-stabilizing agent valproate inhibits the activity of glycogen synthase kinase-3.
Valproic acid (VPA) is a potent broad-spectrum anti-epileptic with demonstrated efficacy in the treatment of bipolar affective disorder. It has previously been demonstrated that both VPA and lithium increase activator protein-1 (AP-1) DNA binding activity, but the mechanisms underlying these effects have not been elucidated. However, it is known that phosphorylation of c-jun by glycogen synthase kinase (GSK)-3beta inhibits AP-1 DNA binding activity, and lithium has recently been demonstrated to inhibit GSK-3beta. These results suggest that lithium may increase AP-1 DNA binding activity by inhibiting GSK-3beta. In the present study, we sought to determine if VPA, like lithium, regulates GSK-3. We have found that VPA concentration-dependently inhibits both GSK-3alpha and -3beta, with significant effects observed at concentrations of VPA similar to those attained clinically. Incubation of intact human neuroblastoma SH-SY5Y cells with VPA results in an increase in the subsequent in vitro recombinant GSK-3beta-mediated 32P incorporation into two putative GSK-3 substrates (approximately 85 and 200 kDa), compatible with inhibition of endogenous GSK-3beta by VPA. Consistent with GSK-3beta inhibition, incubation of SH-SY5Y cells with VPA results in a significant time-dependent increase in both cytosolic and nuclear beta-catenin levels. GSK-3beta plays a critical role in the CNS by regulating various cytoskeletal processes as well as long-term nuclear events and is a common target for both lithium and VPA; inhibition of GSK-3beta in the CNS may thus underlie some of the long-term therapeutic effects of mood-stabilizing agents.
Chen
G
G
Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, Michigan 48201, USA.
Huang
L D
LD
Jiang
Y M
YM
Manji
H K
HK
D018692:Antimanic Agents / Q000494:pharmacology*; D015820:Cadherins / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors*; D002460:Cell Line; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D038362:Glycogen Synthase Kinase 3; D038341:Glycogen Synthase Kinases; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D011994:Recombinant Proteins / Q000378:metabolism; D015534:Trans-Activators; D014635:Valproic Acid / Q000494:pharmacology*; D051176:beta Catenin
D018692:Antimanic Agents; C495270:CTNNB1 protein, human; D015820:Cadherins; D003598:Cytoskeletal Proteins; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D011994:Recombinant Proteins; D015534:Trans-Activators; D051176:beta Catenin; D014635:Valproic Acid; D038341:Glycogen Synthase Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D038362:Glycogen Synthase Kinase 3