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Research ArticleTOXICOLOGY

The Activation of Neuronal Nitric-Oxide Synthase by Various Divalent Cations

John Weaver, Supatra Porasuphatana, Pei Tsai, Guan-Liang Cao, Theodore A. Budzichowski, Linda J. Roman and Gerald M. Rosen
Journal of Pharmacology and Experimental Therapeutics August 2002, 302 (2) 781-786; DOI: https://doi.org/10.1124/jpet.102.035337
John Weaver
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Supatra Porasuphatana
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Pei Tsai
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Guan-Liang Cao
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Theodore A. Budzichowski
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Linda J. Roman
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Gerald M. Rosen
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Abstract

Nitric-oxide synthase (NOS; EC 1.14.13.39) catalyzes the oxidation ofl-arginine to nitric oxide (NO⋅) andl-citrulline via the intermediateNω-hydroxy-l-arginine. Of the three distinct isoforms of NOS that have been characterized, the constitutive neuronal NOS (NOS I) generates NO⋅associated with long-term potentiation (LTP) and early brain development. All of the NOS isoforms contain an N-terminal oxidase and a C-terminal reductase domain connected by a Ca2+/calmodulin binding region. To activate NOS I, Ca2+ has to bind to calmodulin, allowing electron transport through both domains. Calcium ions are tightly regulated in cells. However, a number of other metal ions that bind and activate calmodulin may also activate NOS I. One such metal ion may be Pb2+, which is associated with neurobehavioral and psychological alterations, including the inhibition of LTP. The effect of various divalent cations on NOS I activity was tested, and the results presented herein demonstrate that Pb2+ and Sr2+ can activate NOS I to a level similar to that found for Ca2+. Finally, there is a synergy between Pb2+ and Ca2+ resulting in maximal activation of NOS I using minimal concentrations of both metal ions.

Footnotes

  • This research was supported in part by grants from the National Institutes of Health (RR-12257 to G.M.R., T32-ES07263 to P.T., R25-GM55036 to J.W., and GM52419 to L.J.R.).

  • DOI: 10.1124/jpet.102.035337

  • Abbreviations:
    NO⋅
    nitric oxide
    NOS
    nitric-oxide synthase
    LTP
    long-term potentiation
    BMPO
    5-tert-butoxycarbonyl-5-methyl-1-pyrrolineN-oxide
    H4B
    (6R)-5,6,7,8-tetrahydro-l-biopterin dihydrochloride (tetrahydrobiopterin)
    • Received February 26, 2002.
    • Accepted April 25, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 302 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 302, Issue 2
1 Aug 2002
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Research ArticleTOXICOLOGY

The Activation of Neuronal Nitric-Oxide Synthase by Various Divalent Cations

John Weaver, Supatra Porasuphatana, Pei Tsai, Guan-Liang Cao, Theodore A. Budzichowski, Linda J. Roman and Gerald M. Rosen
Journal of Pharmacology and Experimental Therapeutics August 1, 2002, 302 (2) 781-786; DOI: https://doi.org/10.1124/jpet.102.035337

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Research ArticleTOXICOLOGY

The Activation of Neuronal Nitric-Oxide Synthase by Various Divalent Cations

John Weaver, Supatra Porasuphatana, Pei Tsai, Guan-Liang Cao, Theodore A. Budzichowski, Linda J. Roman and Gerald M. Rosen
Journal of Pharmacology and Experimental Therapeutics August 1, 2002, 302 (2) 781-786; DOI: https://doi.org/10.1124/jpet.102.035337
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