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Lithium Inhibits Glycogen Synthase Kinase-3 by Competition for Magnesium

Ryves, William Jonathan and Harwood, Adrian J. 2001. Lithium Inhibits Glycogen Synthase Kinase-3 by Competition for Magnesium. Biochemical and Biophysical Research Communications 280 (3) , pp. 720-725. 10.1006/bbrc.2000.4169

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
Neuroscience and Mental Health Research Institute (NMHRI)
Subjects: Q Science > Q Science (General)
Publisher: Elsevier
ISSN: 0006-291X
Last Modified: 19 Mar 2016 23:18
URI: http://orca-mwe.cf.ac.uk/id/eprint/46399

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