Document Detail

Metabolism of 3-nitrotyrosine induces apoptotic death in dopaminergic cells.
MedLine Citation:
PMID:  16763020     Owner:  NLM     Status:  MEDLINE    
Intrastriatal injection of 3-nitrotyrosine, which is a biomarker for nitrating oxidants, provokes dopaminergic neuronal death in rats by unknown mechanisms. Herein, we show that extracellular 3-nitrotyrosine is transported via the l-aromatic amino acid transporter in nondopaminergic NT2 cells, whereas in dopaminergic PC12 cells, it is transported by both the l-aromatic amino acid and the dopamine transporters. In both cell lines, 3-nitrotyrosine is a substrate for tyrosine tubulin ligase, resulting in its incorporation into the C terminus of alpha-tubulin. In NT2 cells, incorporation of 3-nitrotyrosine into alpha-tubulin induces a progressive, reversible reorganization of the microtubule architecture. In PC12 cells, 3-nitrotyrosine decreases intracellular dopamine levels and is metabolized by the concerted action of the aromatic amino acid decarboxylase and monoamine oxidase. Intracellular levels of 133 micromol of 3-nitrotyrosine per mole of tyrosine did not alter NT2 viability but induced PC12 apoptosis. The cell death was reversed by caspases and aromatic amino acid decarboxylase and monoamine oxidase inhibitors. 3-Nitrotyrosine induced loss of tyrosine hydroxylase-positive primary rat neurons, which was also prevented by an aromatic amino acid decarboxylase inhibitor. These findings provide a novel mechanism by which products generated by reactive nitrogen species induce dopaminergic neuron death and thus may contribute to the selective neurodegeneration in Parkinson's disease.
Béatrice Blanchard-Fillion; Delphine Prou; Manuela Polydoro; David Spielberg; Elpida Tsika; Zeneng Wang; Stanley L Hazen; Michael Koval; Serge Przedborski; Harry Ischiropoulos
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.    
Journal Detail:
Title:  The Journal of neuroscience : the official journal of the Society for Neuroscience     Volume:  26     ISSN:  1529-2401     ISO Abbreviation:  J. Neurosci.     Publication Date:  2006 Jun 
Date Detail:
Created Date:  2006-06-09     Completed Date:  2006-07-07     Revised Date:  2008-11-21    
Medline Journal Info:
Nlm Unique ID:  8102140     Medline TA:  J Neurosci     Country:  United States    
Other Details:
Languages:  eng     Pagination:  6124-30     Citation Subset:  IM    
Stokes Research Institute, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Amino Acid Transport Systems / metabolism
Apoptosis / physiology*
Aromatic-L-Amino-Acid Decarboxylases / metabolism
Cell Death
Cell Line, Tumor
Cell Physiological Phenomena*
Cell Survival
Cells / metabolism*
Dopamine / metabolism*
Dopamine Plasma Membrane Transport Proteins / metabolism
Mesencephalon / cytology
Microtubules / ultrastructure
Monoamine Oxidase / metabolism
Neurons / physiology
Nitrophenols / metabolism
PC12 Cells
Tubulin / metabolism
Tyrosine / analogs & derivatives*,  metabolism
Grant Support
Reg. No./Substance:
0/Amino Acid Transport Systems; 0/Dopamine Plasma Membrane Transport Proteins; 0/Nitrophenols; 0/Phenylacetates; 0/Tubulin; 10463-20-4/4-hydroxy-5-nitrophenyl acetic acid; 3604-79-3/3-nitrotyrosine; 55520-40-6/Tyrosine; EC Oxidase; EC Decarboxylases

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

Previous Document:  Minimizing polymorphic metabolism in drug discovery: evaluation of the utility of in vitro methods f...
Next Document:  Vasopressin inhibits glutamate release via two distinct modes in the brainstem.