Lithium inhibits glycogen synthase kinase-3 by competition for magnesium.
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 (Mg(2+)), 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 Mg(2+) concentration. We also found that GSK-3 is sensitive to chelation of free Mg(2+) by ATP and is progressively inhibited when ATP concentrations exceed that of Mg(2+). Given the cellular concentrations of ATP and Mg(2+), 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.
Ryves
W J
WJ
MRC Laboratory for Molecular Cell Biology, University College London, Gower Street, London WC1E 6BT, United Kingdom.
Harwood
A J
AJ
D000255:Adenosine Triphosphate / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004023:Dictyostelium / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D038362:Glycogen Synthase Kinase 3; D038341:Glycogen Synthase Kinases; D066298:In Vitro Techniques; D007700:Kinetics; D008094:Lithium / Q000378:metabolism / Q000494:pharmacology*; D008274:Magnesium / Q000378:metabolism*; D011817:Rabbits; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism
D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; D000255:Adenosine Triphosphate; D008094:Lithium; D038341:Glycogen Synthase Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D038362:Glycogen Synthase Kinase 3; D008274:Magnesium