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ToxSci Advance Access originally published online on July 7, 2004
Toxicological Sciences 2004 81(2):325-331; doi:10.1093/toxsci/kfh211
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Toxicological Sciences vol. 81 no. 2 © Society of Toxicology 2004; all rights reserved.

The Effect of Divalent Cations on Neuronal Nitric Oxide Synthase Activity

John Weaver*,{dagger},||,1, Supatra Porasuphatana{ddagger}, Pei Tsai{dagger},||, Guan-Liang Cao{dagger}, Theodore A. Budzichowski*, Linda J. Roman§ and Gerald M. Rosen{dagger},¶,||

* Department of Chemistry, University of Maryland Baltimore County, Baltimore, Maryland 21250; {dagger} Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, Maryland 21201; {ddagger} Department of Toxicology, Faculty of Pharmaceutical Science, Khon Kaen University, Khon Kaen 40002, Thailand; § Department of Biochemistry, The University of Texas Health Science Center at San Antonio, San Antonio, Texas 78230; Medical Biotechnology Center, University of Maryland Biotechnology Institute, Baltimore, Maryland 21201; and || Center for Low Frequency EPR for In Vivo Physiology, University of Maryland, Baltimore, Maryland 21201

Received June 7, 2004; accepted June 30, 2004

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.

Key Words: nitric oxide; superoxide; NOS I; calmodulin; divalent cations; metal toxicity.


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