Stambolic, V., Ruel, L. &Woodgett, J.R. Lithium inhibits glycogen synthase kinase-3 activity and mimics Wingless signaling in intact cells. Curr. Biol. 6, 1664-1668

Ontario Cancer Institute, Toronto, Canada.
Current Biology (Impact Factor: 9.57). 01/1997; 6(12):1664-8. DOI: 10.1016/S0960-9822(02)70790-2
Source: PubMed


Exposing eukaryotic cells to lithium ions (Li+) during development has marked effects on cell fate and organization. The phenotypic consequences of Li+ treatment on Xenopus embryos and sporulating Dictyostelium are similar to the effects of inhibition or disruption, respectively, of a highly conserved protein serine/threonine kinase, glycogen synthase kinase-3 (GSK-3). In Drosophila, the GSK-3 homologue is encoded by zw3sgg, a segment-polarity gene involved in embryogenesis that acts downstream of wg. In higher eukaryotes, GSK-3 has been implicated in signal transduction pathways downstream of phosphoinositide 3-kinase and mitogen-activated protein kinases.
We investigated the effect of Li+ on the activity of the GSK-3 family. At physiological doses, Li+ inhibits the activity of human GSK-3 beta and Drosophila Zw3Sgg, but has no effect on other protein kinases. The effect of Li+ on GSK-3 is reversible in vitro. Treatment of cells with Li+ inhibits GSK-3-dependent phosphorylation of the microtubule-associated protein Tau. Li+ treatment of Drosophila S2 cells and rat PC12 cells induces accumulation of cytoplasmic Armadillo/beta-catenin, demonstrating that Li+ can mimic Wingless signalling in intact cells, consistent with its inhibition of GSK-3.
Li+ acts as a specific inhibitor of the GSK-3 family of protein kinases in vitro and in intact cells, and mimics Wingless signalling. This reveals a possible molecular mechanism of Li+ action on development and differentiation.

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    • "Valproic acid (VPA) and lithium chloride (LiCl) are two mood-stabilizing drugs used to treat patients with bipolar disorder (Kazantsev and Thompson 2008; Li et al. 2012). It has been reported that the major pharmacological actions of VPA are to inhibit histone deacetylase (HDAC) and glycogen synthase kinase-3 (GSK-3) activities (Phiel et al. 2001; Werstuck et al. 2004), while LiCl is the inhibitor of GSK-3 (Stambolic et al. 1996; Zhang et al. 2003). Recent studies also demonstrate that VPA or LiCl treatment increases the expression of brain-derived neurotrophic factor (BDNF) (Yasuda et al. 2007). "

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    • "Inhibition of GSK3b has been suggested to promote adult hippocampal neurogenesis in vitro and in vivo (Morales-Garcia et al., 2012). Lithium promotes phosphorylation and inactivation of GSK3b (Klein & Melton, 1996; Stambolic et al., 1996). From these findings the prediction is that lithium treatment promotes adult hippocampal neurogenesis in wild-type mice. "
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    • "Other types of GSK-3 inhibitors are lithium salt and substrate-competitive peptides such as L803-mts. Lithium competes with magnesium for a binding site on the GSK-3 catalytic domain [110] [111] [112]. The clinical relevance of lithium use as a potential cancer-preventive agent was from an early report [28], which showed that in a cohort of 609 psychiatric patients treated with lithium, cancer incidence was significantly lower than that in 2396 controls, and an inverted trend of cancer incidence was associated with lithium doses. "
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