The effect of divalent cations on neuronal nitric oxide synthase activity

John Weaver, Supatra Porasuphatana, Pei Tsai, Guan Liang Cao, Theodore A. Budzichowski, Linda J. Roman, Gerald M. Rosen

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

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 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.

Original languageEnglish (US)
Pages (from-to)325-331
Number of pages7
JournalToxicological Sciences
Volume81
Issue number2
DOIs
StatePublished - Oct 2004

Keywords

  • Calmodulin
  • Divalent cations
  • Metal toxicity
  • NOS I
  • Nitric oxide
  • Superoxide

ASJC Scopus subject areas

  • Toxicology

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