Inhibition of glycogen synthase kinase-3: A potential therapeutic target of lithium

Glycogen synthase kinase-3 (GSK3) is inhibited by the mood stabilizer lithium in two ways. First, lithium directly inhibits the enzyme. This direct inhibitory effect is amplified in vivo by an increase in the inhibitory phosphorylation of an N-terminal serine in GSK3, enabling low concentrations of lithium to significantly modulate GSK3. Inhibition of GSK3 by lithium has multiple effects on cellular functions due to the numerous substrates of GSK3, any of which may contribute to the mood stabilizing action of lithium. These include regulation of neural plasticity through changes in cellular architecture and remodelling events, regulation of gene expression through modulation of the activities of transcription factors, and regulation of cellular responses to stress and the ensuing modulation of cell survival. The manifold influences of GSK3 on the dynamics of neuronal function provide substantial support for the proposal that GSK3 may be a key target for the therapeutic actions of lithium.