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Ammonia induces MK‐801‐sensitive nitration and phosphorylation of protein tyrosine residues in rat astrocytes
Author(s) -
Schliess Freimut,
Görg Boris,
Fischer Richard,
Desjardins Paul,
Bidmon Hans J.,
Herrmann Andreas,
Butterworth Roger F.,
Zilles Karl,
Häussinger Dieter
Publication year - 2002
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.01-0862fje
Subject(s) - chemistry , biochemistry , tyrosine , neurotoxicity , astrocyte , biology , endocrinology , organic chemistry , toxicity , central nervous system
Astrocytes play a key role in the pathogenesis of ammonia‐induced neurotoxicity and hepatic encephalopathy. As shown here, ammonia induces protein tyrosine nitration in cultured rat astrocytes, which is sensitive to the N‐methyl‐D‐aspartate (NMDA) receptor antagonist MK‐801. A similar pattern of nitrated proteins is produced by NMDA. Ammonia‐induced tyrosine nitration depends on a rise in [Ca 2+ ]i, IκB degradation, and NO synthase (iNOS) induction, which are prevented by MK‐801 and the intracellular Ca 2+ chelator 1,2‐bis(oaminophenoxy)ethane‐N,N,N',N'‐tetraacetic acid (BAPTA‐AM). Moreover, the increase in tyrosine nitration is blunted by L‐NMMA, 1400W, uric acid, Cu, Zn‐superoxide dismutase/catalase treatment, and methionine‐sulfoximine, which indicate the involvement of reactive nitrogen intermediates and intracellular glutamine accumulation. Such reactive nitrogen intermediates additionally mediate ammonia‐induced phosphorylation of the MAP‐kinases Erk1/Erk‐2 and p38 MAPK . Among the proteins, which are tyrosine‐nitrated by ammonia, glyceraldehyde‐3‐phosphate dehydrogenase, the peripheral‐type benzodiazepine receptor, Erk‐1, and glutamine synthetase are identified. Ammonia‐induced nitration of glutamine synthetase is associated with a loss of enzymatic activity. Astroglial protein tyrosine nitration is found in brains from rats after acute ammonia‐intoxication or after portacaval anastomosis, indicating the in vivo relevance of the present findings. The production of reactive nitrogen intermediates and protein tyrosine nitration may alter astrocyte function and contribute to ammonia neurotoxicity.