Regulation of calcineurin by metal ions. Mechanism of activation by Ni2+ and an enhanced response to Ca2+/calmodulin.
Calcineurin possesses phosphatase activity towards both protein (Stewart, A.A., Ingebritsen , T.S., Manalan , A., Klee , C.B., and Cohen, P. (1982) FEBS Lett. 137, 80-84) and nonprotein substrates ( Pallen , C.J., and Wang, J.H. (1983) J. Biol. Chem. 258, 8550-8553). These phosphatase activities are divalent cation-dependent and stimulated by calmodulin. We have utilized the nonprotein chromogenic substrate p-nitrophenyl phosphate to investigate the effects of several divalent metal ions on calcineurin activity and have found that Ni2+ is the best activator of calcineurin both in the presence and absence of calmodulin. A slightly less potent activator is Mn2+. Although the mechanisms and extents of activation stimulated by these two metal ions are different, we present evidence to suggest a competition for binding to the enzyme. Pretreatment of calcineurin with either of these two metal ions enhances the activation of calcineurin by Ca2+/calmodulin and may be a physiological mechanism by which calcineurin activity is regulated by Ca2+.
D000818:Animals; D001921:Brain / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D002147:Calmodulin / Q000378:metabolism*; D002148:Calmodulin-Binding Proteins; D002413:Cations, Divalent; D002417:Cattle; D004492:Edetic Acid / Q000494:pharmacology; D007700:Kinetics; D008345:Manganese / Q000494:pharmacology; D009532:Nickel / Q000494:pharmacology*; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*
D002147:Calmodulin; D002148:Calmodulin-Binding Proteins; D002413:Cations, Divalent; D008345:Manganese; D009532:Nickel; D004492:Edetic Acid; D010749:Phosphoprotein Phosphatases; D002118:Calcium