Get access

GSK-3 activity in neocortical cells is inhibited by lithium but not carbamazepine or valproic acid

Authors


  • The authors of this paper do not have any commercial associations that might pose a conflict of interest in connection with this manuscript.

Dr Robin SB Williams, Department of Biology and The Wolfson Institute for Biomedical Research, Gower St, University College London, WC1E6BT, London, UK. Fax: 44 20 7679 7096;
e-mail: robin.williams@ucl.ac.uk

Abstract

Objectives:  Lithium (Li+) has been suggested to target the enzyme glycogen synthase kinase 3 (GSK-3) as a mechanism of mood stabilization. Inhibition of GSK-3 by a second mood-stabilizer, valproic acid (VPA), has also been reported, but this effect is dependent on cell type. It is currently unknown if carbamazepine (CBZ) inhibits GSK-3 activity. We have sought to compare the inhibitory effect of Li+, VPA and CBZ on GSK-3 activity.

Methods:  We treated rat primary cultured neurones at three times therapeutic drug concentration with CBZ, VPA and Li+ and examined changes in GSK-3 protein levels, activity and phosphorylation of downstream targets. To eliminate a possible direct effect of these drugs at higher concentrations, we also looked for direct inhibition of both GSK-3 isoforms at a range of concentrations.

Results:  CBZ, VPA and Li+ did not change the levels of the GSK-3 or produce an irreversible in vivo effect on GSK-3 activity. Only Li+ inhibited the phosphorylation of a cytoskeletal target of GSK-3, tau, whereas CBZ and VPA did not. Surprisingly, none of these drugs altered β-catenin levels in these cells, a process attenuated by GSK-3 activity. Finally, only Li+ directly inhibits GSK-3 activity (both α and β isoforms) at therapeutic levels in direct biochemical assays.

Conclusion:  Thus we show that neither GSK-3 nor the altered GSK-3 signalling pathway can provide a common mechanism of action of mood-stabilizing drugs in the mammalian brain.

Ancillary