Ni2+, double-acting inhibitor of neuronal nitric oxide synthase interfering with L-arginine binding and Ca2+/calmodulin-dependent enzyme activation

Ni2+, a toxic and carcinogenic pollutant and one of the leading causes of c ontact dermatitis, is shown to inhibit neuronal nitric oxide synthase (nNOS ) in a competitive, reversible manner with respect to the substrate L-argin ine (K-i = 30 +/- 4 muM). The IC50 values were dependent on calmodulin (CaM ) concentration, but proved independent of Ca2+, tetrahydrobiopterin (BH,) and other essential cofactors, Ni2+ also inhibited CaM-dependent cytochrome c reduction, NADPH oxidation, and H2O2 production by nNOS, Overall, the ac tion profile of Ni2+ was suggestive of an unusual, double-acting inhibitor of nNOS affecting L-arginine-binding and Ca2+/CaM-dependent enzyme activati on. (C) 2001 Academic Press.