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Molecular Pharmacology

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Research ArticleArticle

Inhibition of Acetylcholine Synthesis and Tyrosine Nitration Induced by Peroxynitrite Are Differentially Prevented by Antioxidants

Lydie Guermonprez, Claire Ducrocq and Yvette Morot Gaudry-Talarmain
Molecular Pharmacology October 2001, 60 (4) 838-846;
Lydie Guermonprez
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Claire Ducrocq
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Yvette Morot Gaudry-Talarmain
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Abstract

Evidence of an overload of reactive oxygen species and peroxynitrite, a derivative of nitric oxide, in sporadic amyotrophic lateral sclerosis suggests that peroxynitrite could impair cholinergic functions. Because of the impossibility of obtaining synaptosomes from vertebrate neuromuscular junctions, we used cholinergic synaptosomes purified fromTorpedo marmorata electroneurons to characterize the defects triggered by peroxynitrite in more detail. Addition of peroxynitrite or its donor 3-morpholinosydnonimine abolished high-affinity choline uptake and synthesis of acetylcholine from acetate. T. marmorata choline acetyltransferase (ChAT) was impaired to the same extent as bovine brain ChAT. A hallmark of peroxynitrite action is the nitration of tyrosine residues in proteins. Peroxynitrite induced a concentration-dependent appearance of nitrotyrosines in several neuronal proteins from synaptosomes and, more readily, from synaptic vesicles. Peroxynitrite also triggered tyrosine nitrations in purified ChAT. Peroxynitrite-dependent nitrations were impaired when synaptosomes were pretreated with thioreductants (glutathione, N-acetyl cysteine, dithiothreitol) or antioxidants (uric acid, melatonin, bovine serum albumin, desferrioxamine). Deleterious effects of peroxynitrite on choline transport and ChAT activity were prevented by the thioreductants but only partially by the antioxidants, suggesting a mechanism other than tyrosine nitration, which may involve cysteine oxidation. Further development of protective agents acting on choline transport and on ChAT activity may offer interesting therapeutic possibilities with respect to cholinergic dysfunction occurring in neurodegenerative diseases.

Footnotes

  • This work was supported by the Centre National de la Recherche Scientifique and the Institut de Recherches Internationales Servier.

  • Abbreviations:
    ONOO−
    peroxynitrite
    ACh
    acetylcholine
    SIN-1
    3-morpholinosydnonimine
    CoA
    Coenzyme A
    ChAT
    choline acetyltransferase
    VAMP/synaptobrevin
    vesicular-associated membrane protein
    TCA
    trichloroacetic acid
    BSA
    bovine serum albumin
    PAGE
    polyacrylamide gel electrophoresis
    ECL
    enhanced chemiluminescence
    GSH
    glutathione
    NAC
    N-acetylcysteine
    DTT
    dithiothreitol
    • Received February 12, 2001.
    • Accepted June 29, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 60 (4)
Molecular Pharmacology
Vol. 60, Issue 4
1 Oct 2001
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Research ArticleArticle

Inhibition of Acetylcholine Synthesis and Tyrosine Nitration Induced by Peroxynitrite Are Differentially Prevented by Antioxidants

Lydie Guermonprez, Claire Ducrocq and Yvette Morot Gaudry-Talarmain
Molecular Pharmacology October 1, 2001, 60 (4) 838-846;

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Research ArticleArticle

Inhibition of Acetylcholine Synthesis and Tyrosine Nitration Induced by Peroxynitrite Are Differentially Prevented by Antioxidants

Lydie Guermonprez, Claire Ducrocq and Yvette Morot Gaudry-Talarmain
Molecular Pharmacology October 1, 2001, 60 (4) 838-846;
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