Glycogen synthase kinase-3 inhibition by lithium and beryllium suggests the presence of two magnesium binding sites.
Lithium inhibits (Li(+)) glycogen synthase kinase-3 (GSK-3) by competition for magnesium (Mg(2+)), but not ATP or substrate. Here, we show that the group II metal ion beryllium (Be(2+)) is a potent inhibitor of GSK-3 and competes for both Mg(2+) and ATP. Be(2+) also inhibits the related protein kinase cdc2 at similar potency, but not MAP kinase 2. To compare the actions of Li(+) and Be(2+) on GSK-3, we have devised a novel dual inhibition analysis. When Be(2+) and ADP are present together each interferes with the action of the other, indicating that both agents inhibit GSK-3 at the ATP binding site. In contrast, Li(+) exerts no interference with ADP inhibition or vice versa. We find, however, that Li(+) and Be(2+) do interfere with each other. These results suggest that Be(2+) competes for two distinct Mg(2+) binding sites: one is Li(+)-sensitive and the other, which is Li(+)-insensitive, binds the Mg:ATP complex.
Ryves
W Jonathan
WJ
MRC Laboratory for Molecular Cell Biology, University College London, Gower Street, London, WC1E 6BT, United Kingdom.
Dajani
Rana
R
Pearl
Laurence
L
Harwood
Adrian J
AJ
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000378:metabolism; D001608:Beryllium / Q000494:pharmacology*; D001665:Binding Sites; D001667:Binding, Competitive; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D038362:Glycogen Synthase Kinase 3; D038341:Glycogen Synthase Kinases; D006801:Humans; D007700:Kinetics; D018021:Lithium Chloride / Q000494:pharmacology*; D008274:Magnesium / Q000378:metabolism*
D004791:Enzyme Inhibitors; C032776:beryllium chloride; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D038341:Glycogen Synthase Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D038362:Glycogen Synthase Kinase 3; D018021:Lithium Chloride; D008274:Magnesium; D001608:Beryllium