Mood stabilizers, glycogen synthase kinase-3β and cell survival

Glycogen synthase kinase-3β (GSK3β) is a central figure in many intracellular signaling systems and is directly regulated by lithium. Substantial evidence now indicates that an important property of the mood stabilizer, lithium, is to influence GSK3β-linked signaling pathways. This raises the possibility that other mood stabilizers act in a similar manner, which may include modulation of signaling systems leading to GSK3β, direct regulation of GSK3β or regulation of signaling intermediates downstream of GSK3β. Downstream targets of GSK3β, and thus potential targets of mood stabilizers, are several key transcription factors, including β-catenin, AP-1, cyclic AMP-response element binding protein, NFκB, Myc, heat shock factor-1, nuclear factor of activated T-cells and CCAAT/enhancer-binding proteins. GSK3β also is an important modulator of cell death, which may be a consequence of its regulatory effects on transcription factor activities. GSK3β facilitates apoptosis, and lithium's inhibition of GSK3β supports cell survival. Thus, signaling systems determining cell fate appear to be important targets of mood stabilizers, and these may include signaling pathways encompassing GSK3β, including transcription factors regulated by GSK3β.