Ni(2+), a double-acting inhibitor of neuronal nitric oxide synthase interfering with L-arginine binding and Ca(2+)/calmodulin-dependent enzyme activation.
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 microM). 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.
Palumbo
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A
Zoological Station "Anton Dohrn", Villa Comunale, Naples, I-80121, Italy. palumbo@alpha.szn.it
Astarita
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G
Picardo
M
M
d'Ischia
M
M
D000818:Animals; D001120:Arginine / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D002147:Calmodulin / Q000378:metabolism*; D002384:Catalysis; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007700:Kinetics; D051379:Mice; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors; D009532:Nickel / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I; D011485:Protein Binding; D051381:Rats; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism
D002147:Calmodulin; D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; C022838:nickel chloride; D009532:Nickel; D001120:Arginine; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496321:Nos1 protein, mouse; C496322:Nos1 protein, rat; D019255:NADPH Oxidases; D002118:Calcium