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Lithium Inhibits Glycogen Synthase Kinase-3 by Competition for Magnesium

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Abstract

The mechanism by which lithium (Li+) inhibits the protein kinase glycogen synthase kinase-3 (GSK-3) is unknown. Here, we demonstrate that Li+ is a competitive inhibitor of GSK-3 with respect to magnesium (Mg2+), but not to substrate or ATP. This mode of inhibition is conserved between mammalian and Dictyostelium GSK-3 isoforms, and is not experienced with other group I metal ions. As a consequence, the potency of Li+ inhibition is dependent on Mg2+ concentration. We also found that GSK-3 is sensitive to chelation of free Mg2+ by ATP and is progressively inhibited when ATP concentrations exceed that of Mg2+. Given the cellular concentrations of ATP and Mg2+, our results indicate that Li+ will have a greater effect on GSK-3 activity in vivo than expected from in vitro studies and this may be a factor relevant to its use in the treatment of depression.

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    Abbreviations used: GSK-3β; recombinant rabbit glycogen synthase kinase-3β, GSK-3α; glycogen synthase kinase-3α purified from rabbit skeletal muscle GskA; the Dictyostelium homologue of GSK-3, cdc2; p24 cdc2/cyclin B dependent protein kinase. ATP; adenosine 5′-triphosphate, DTT; dithiothreitol.

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