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GSK‐3 activity in neocortical cells is inhibited by lithium but not carbamazepine or valproic acid
Author(s) -
Jonathan Ryves W,
Dalton Emma C,
Harwood Adrian J,
Williams Robin SB
Publication year - 2005
Publication title -
bipolar disorders
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.285
H-Index - 129
eISSN - 1399-5618
pISSN - 1398-5647
DOI - 10.1111/j.1399-5618.2005.00194.x
Subject(s) - gsk 3 , valproic acid , carbamazepine , lithium (medication) , chemistry , pharmacology , anticonvulsant , glycogen synthase , mechanism of action , gsk3b , phosphorylation , biochemistry , epilepsy , in vitro , endocrinology , biology , neuroscience
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.