Document Detail


NMDA receptor regulation of nNOS phosphorylation and induction of neuron death.
MedLine Citation:
PMID:  14643384     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Stimulation of NMDA receptors activates neuronal nitric oxide synthase (nNOS) and the production of nitric oxide (NO). Dephosphorylation of nNOS increases nNOS enzymatic activity. We have examined the regulation of nNOS phosphorylation in rat cortical neurons following NMDA receptor activation. We show that nNOS is constitutively phosphorylated and that NMDA receptor activation decreases the level of nNOS phosphorylation by a mechanism that is blocked specifically by NMDA receptor antagonists and inhibitors of the Ca2+-regulated phosphatases calcineurin and PP1/PP2A. Using quantitative digital microscopy, we show that NMDA receptor activation induces the accumulation of nitrotyrosine, a measure of nNOS activity, and TdT-mediated fluorescein-dUTP nick end labeling (TUNEL) positivity, a measure of cell death. A calcineurin inhibitor blocked the increase in both TUNEL and nitrotyrosine positivity. Notably, TUNEL was increased in those neurons that were most strongly positive for nitrotyrosine. We conclude that NMDA receptor activation induces death of neurons by a cell autonomous pathway involving nNOS dephosphorylation by a calcineurin-dependent mechanism.
Authors:
Gerald A Rameau; Ling-Yu Chiu; Edward B Ziff
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Neurobiology of aging     Volume:  24     ISSN:  0197-4580     ISO Abbreviation:  Neurobiol. Aging     Publication Date:  2003 Dec 
Date Detail:
Created Date:  2003-12-03     Completed Date:  2004-03-11     Revised Date:  2008-11-21    
Medline Journal Info:
Nlm Unique ID:  8100437     Medline TA:  Neurobiol Aging     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1123-33     Citation Subset:  IM    
Affiliation:
Department of Biochemistry, Howard Hughes Medical Institute, NYU School of Medicine, New York, NY 10016, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Apoptosis / drug effects,  physiology*
Calcineurin / antagonists & inhibitors,  metabolism
Cells, Cultured
Enzyme Inhibitors / pharmacology
Excitatory Amino Acid Agonists / pharmacology
Excitatory Amino Acid Antagonists / pharmacology
In Situ Nick-End Labeling
Nerve Degeneration / enzymology*,  physiopathology
Neurodegenerative Diseases / enzymology,  physiopathology
Neurons / drug effects,  enzymology*
Nitric Oxide Synthase / metabolism*
Nitric Oxide Synthase Type I
Phosphoprotein Phosphatases / antagonists & inhibitors,  metabolism
Phosphorylation / drug effects
Rats
Receptors, N-Methyl-D-Aspartate / drug effects,  metabolism*
Tyrosine / analogs & derivatives*,  metabolism
Grant Support
ID/Acronym/Agency:
ES00260/ES/NIEHS NIH HHS; NS 07457-04/NS/NINDS NIH HHS; R01 AG13620/AG/NIA NIH HHS
Chemical
Reg. No./Substance:
0/Enzyme Inhibitors; 0/Excitatory Amino Acid Agonists; 0/Excitatory Amino Acid Antagonists; 0/Receptors, N-Methyl-D-Aspartate; 3604-79-3/3-nitrotyrosine; 55520-40-6/Tyrosine; EC 1.14.13.39/Nitric Oxide Synthase; EC 1.14.13.39/Nitric Oxide Synthase Type I; EC 1.14.13.39/Nos1 protein, rat; EC 3.1.3.16/Calcineurin; EC 3.1.3.16/Phosphoprotein Phosphatases

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


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