Jope R S, Bijur G N
Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL 35294-0017, USA.
Mol Psychiatry. 2002;7 Suppl 1:S35-45. doi: 10.1038/sj.mp.4001017.
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.
糖原合酶激酶-3β（GSK3β）是许多细胞内信号系统的核心分子，且直接受锂的调控。现在大量证据表明，情绪稳定剂锂的一个重要特性是影响与GSK3β相关的信号通路。这就增加了其他情绪稳定剂也以类似方式起作用的可能性，这可能包括调节通向GSK3β的信号系统、直接调控GSK3β或调控GSK3β下游的信号中间体。GSK3β的下游靶点，因而也是情绪稳定剂的潜在靶点，是几个关键转录因子，包括β-连环蛋白、AP-1、环磷酸腺苷反应元件结合蛋白、核因子κB、Myc、热休克因子-1、活化T细胞核因子以及CCAAT/增强子结合蛋白。GSK3β也是细胞死亡的重要调节因子，这可能是其对转录因子活性的调控作用的结果。GSK3β促进细胞凋亡，而锂对GSK3β的抑制作用则支持细胞存活。因此，决定细胞命运的信号系统似乎是情绪稳定剂的重要靶点，这些可能包括包含GSK3β的信号通路，包括受GSK3β调控的转录因子。
