The mood-stabilizing agent valproate inhibits the activity of glycogen synthase kinase-3.

Abstract

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.

• Authors: G Chen, L D Huang, Y M Jiang, H K Manji
• Journal: Journal of neurochemistry (J Neurochem) Vol. 72 Issue 3 Pg. 1327-30 (Mar 1999) ISSN: 0022-3042 [Print] England
• PMID: 10037507 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antimanic Agents
• CTNNB1 protein, human
• Cadherins
• Cytoskeletal Proteins
• Enzyme Inhibitors
• Isoenzymes
• Recombinant Proteins
• Trans-Activators
• beta Catenin
• Valproic Acid
• Glycogen Synthase Kinases
• Calcium-Calmodulin-Dependent Protein Kinases
• Glycogen Synthase Kinase 3

Topics

• Antimanic Agents (pharmacology)
• Cadherins (metabolism)
• Calcium-Calmodulin-Dependent Protein Kinases (antagonists & inhibitors)
• Cell Line
• Cytoskeletal Proteins (metabolism)
• Enzyme Inhibitors (pharmacology)
• Glycogen Synthase Kinase 3
• Glycogen Synthase Kinases
• Humans
• Isoenzymes (antagonists & inhibitors)
• Recombinant Proteins (metabolism)
• Trans-Activators
• Valproic Acid (pharmacology)
• beta Catenin