TY - JOUR
T1 - The effect of divalent cations on neuronal nitric oxide synthase activity
AU - Weaver, John
AU - Porasuphatana, Supatra
AU - Tsai, Pei
AU - Cao, Guan Liang
AU - Budzichowski, Theodore A.
AU - Roman, Linda J.
AU - Rosen, Gerald M.
N1 - Funding Information:
This research was supported in part by grants from the National Institutes of Health, EB-2034 (G.M.R., J.W.), R25-GM55036 (J.W.), AG-20445 (P.T.) and GM52419, and from the Robert A. Welch Foundation, grant AQ1192 (L.J.R.).
PY - 2004/10
Y1 - 2004/10
N2 - Neuronal nitric oxide synthase (NOS I) is a Ca2+/calmodulin-binding enzyme that generates nitric oxide (NO•) and L-citrulline from the oxidation of L-arginine, and superoxide (O2•-) from the one-electron reduction of oxygen (O2). Nitric oxide in particular has been implicated in many physiological processes, including vasodilator tone, hypertension, and the development and properties of neuronal function. Unlike Ca2+, which is tightly regulated in the cell, many other divalent cations are unfettered and can compete for the four Ca2+ binding sites on calmodulin. The results presented in this article survey the effects of various divalent metal ions on NOS I-mediated catalysis. As in the case of Ca2+, we demonstrate that Ni2+, Ba2+, and Mn2+ can activate NOS I to metabolize L-arginine to L-citrulline and NO•, and afford O2•- in the absence of L-arginine. In contrast, Cd2+ did not activate NOS I to produce either NO• or O2•-, and the combination of Ca2+ and either Cd2+, Ni2+, or Mn2+ inhibited enzyme activity. These interactions may initiate cellular toxicity by negatively affecting NOS I activity through production of NO•, O2- and products derived from these free radicals.
AB - Neuronal nitric oxide synthase (NOS I) is a Ca2+/calmodulin-binding enzyme that generates nitric oxide (NO•) and L-citrulline from the oxidation of L-arginine, and superoxide (O2•-) from the one-electron reduction of oxygen (O2). Nitric oxide in particular has been implicated in many physiological processes, including vasodilator tone, hypertension, and the development and properties of neuronal function. Unlike Ca2+, which is tightly regulated in the cell, many other divalent cations are unfettered and can compete for the four Ca2+ binding sites on calmodulin. The results presented in this article survey the effects of various divalent metal ions on NOS I-mediated catalysis. As in the case of Ca2+, we demonstrate that Ni2+, Ba2+, and Mn2+ can activate NOS I to metabolize L-arginine to L-citrulline and NO•, and afford O2•- in the absence of L-arginine. In contrast, Cd2+ did not activate NOS I to produce either NO• or O2•-, and the combination of Ca2+ and either Cd2+, Ni2+, or Mn2+ inhibited enzyme activity. These interactions may initiate cellular toxicity by negatively affecting NOS I activity through production of NO•, O2- and products derived from these free radicals.
KW - Calmodulin
KW - Divalent cations
KW - Metal toxicity
KW - NOS I
KW - Nitric oxide
KW - Superoxide
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U2 - 10.1093/toxsci/kfh211
DO - 10.1093/toxsci/kfh211
M3 - Article
C2 - 15240894
AN - SCOPUS:5744240626
VL - 81
SP - 325
EP - 331
JO - Toxicological Sciences
JF - Toxicological Sciences
SN - 1096-6080
IS - 2
ER -