Mood stabilizers, glycogen synthase kinase-3beta and cell survival.

Glycogen synthase kinase-3beta (GSK3beta) 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 GSK3beta-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 GSK3beta, direct regulation of GSK3beta or regulation of signaling intermediates downstream of GSK3beta. Downstream targets of GSK3beta, and thus potential targets of mood stabilizers, are several key transcription factors, including beta-catenin, AP-1, cyclic AMP-response element binding protein, NFkappaB, Myc, heat shock factor-1, nuclear factor of activated T-cells and CCAAT/enhancer-binding proteins. GSK3beta also is an important modulator of cell death, which may be a consequence of its regulatory effects on transcription factor activities. GSK3beta facilitates apoptosis, and lithium's inhibition of GSK3beta supports cell survival. Thus, signaling systems determining cell fate appear to be important targets of mood stabilizers, and these may include signaling pathways encompassing GSK3beta, including transcription factors regulated by GSK3beta.