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

Abstract Ni 2+ , a toxic and carcinogenic pollutant and one of the leading causes of contact dermatitis, is shown to inhibit neuronal nitric oxide synthase(nNOS) in a competitive, reversible manner with respect to the substrate l -arginine ( K i = 30 ± 4 μM). The IC 50 values were dependent on calmodulin (CaM) concentration, but proved independent of Ca 2+ , tetrahydrobiopterin(BH 4 ) and other essential cofactors. Ni 2+ also inhibited CaM-dependent cytochrome c reduction, NADPH oxidation, and H 2 O 2 production by nNOS. Overall, the action profile of Ni 2+ was suggestive of an unusual, double-acting inhibitor of nNOS affecting l -arginine-binding and Ca 2+ /CaM-dependent enzyme activation.