Lithium inhibits glycogen synthase kinase-3 by competition for magnesium

Biochem Biophys Res Commun. 2001 Jan 26;280(3):720-5. doi: 10.1006/bbrc.2000.4169.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Adenosine Triphosphate / pharmacology
  • Animals
  • Binding, Competitive
  • Calcium-Calmodulin-Dependent Protein Kinases / antagonists & inhibitors*
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism
  • Dictyostelium / enzymology
  • Enzyme Inhibitors / metabolism
  • Enzyme Inhibitors / pharmacology*
  • Glycogen Synthase Kinase 3
  • Glycogen Synthase Kinases
  • In Vitro Techniques
  • Kinetics
  • Lithium / metabolism
  • Lithium / pharmacology*
  • Magnesium / metabolism*
  • Rabbits
  • Recombinant Proteins / antagonists & inhibitors
  • Recombinant Proteins / metabolism


  • Enzyme Inhibitors
  • Recombinant Proteins
  • Adenosine Triphosphate
  • Lithium
  • Glycogen Synthase Kinases
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Glycogen Synthase Kinase 3
  • Magnesium