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+.