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ToxSci Advance Access published online on July 7, 2004
Toxicological Sciences, doi:10.1093/toxsci/kfh211
Toxicological Sciences © Society of Toxicology 2004; all rights reserved
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Received June 7, 2004
Accepted June 30, 2004

Environmental Toxicology

The Effect of Divalent Cations on Neuronal Nitric Oxide Synthase Activity

John Weaver 1*, Supatra Porasuphatana 2, Pei Tsai 3, Guan-Liang Cao 4, Theodore A. Budzichowski 5, Linda J. Roman 6, Gerald M. Rosen 7

1 Department of Chemistry, University of Maryland Baltimore County, Baltimore, MD 21250; Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD 21201; Center for Low Frequency EPR for In Vivo Physiology, University of Maryland, Baltimore, MD 21201
2 Department of Toxicology, Faculty of Pharmaceutical Science, Khon Kaen University, Khon Kaen 40002, Thailand
3 Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD 21201; Center for Low Frequency EPR for In Vivo Physiology, University of Maryland, Baltimore, MD 21201
4 Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD 21201
5 Department of Chemistry, University of Maryland Baltimore County, Baltimore, MD 21250
6 Department of Biochemistry, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78230
7 Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD 21201; Medical Biotechnology Center, University of Maryland Biotechnology Institute, Baltimore, MD 21201; Center for Low Frequency EPR for In Vivo Physiology, University of Maryland, Baltimore, MD 21201

* To whom correspondence should be addressed. E-mail: jeav001{at}umaryland.edu.


  Abstract

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 herein survey the effect various divalent metal ions have 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 impacting NOS I activity through production of NO•, O2•- and products derived from these free radicals.

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