| NMDA receptor-nitric oxide transmission mediates neuronal iron homeostasis via the GTPase Dexras1. | |
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MedLine Citation:
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PMID: 16908409 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Dexras1 is a 30 kDa G protein in the Ras subfamily whose discovery was based on its pronounced inducibility by the glucocorticoid dexamethasone. It binds to neuronal nitric oxide synthase (nNOS) via the adaptor protein CAPON, eliciting S-nitrosylation and activation of Dexras1. We report that Dexras1 binds to the peripheral benzodiazepine receptor-associated protein (PAP7), a protein of unknown function that binds to cyclic AMP-dependent protein kinase and the peripheral benzodiazepine receptor. PAP7 in turn binds to the divalent metal transporter (DMT1), an iron import channel. We have identified a signaling cascade in neurons whereby stimulation of NMDA receptors activates nNOS, leading to S-nitrosylation and activation of Dexras1, which, via PAP7 and DMT1, physiologically induces iron uptake. As selective iron chelation prevents NMDA neurotoxicity in cortical cultures, the NMDA-NO-Dexras1-PAP7-DMT1-iron uptake signaling cascade also appears to mediate NMDA neurotoxicity. |
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Authors:
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Jaime H Cheah; Sangwon F Kim; Lynda D Hester; Kathleen W Clancy; Stanley E Patterson; Vassilios Papadopoulos; Solomon H Snyder |
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Publication Detail:
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Type: Comparative Study; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Neuron Volume: 51 ISSN: 0896-6273 ISO Abbreviation: Neuron Publication Date: 2006 Aug |
Date Detail:
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Created Date: 2006-08-15 Completed Date: 2006-09-26 Revised Date: 2011-08-25 |
Medline Journal Info:
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Nlm Unique ID: 8809320 Medline TA: Neuron Country: United States |
Other Details:
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Languages: eng Pagination: 431-40 Citation Subset: IM |
Affiliation:
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Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Adaptor Proteins, Signal Transducing Aldehydes / pharmacology Animals Blotting, Western / methods Cation Transport Proteins / metabolism Cells, Cultured Cerebral Cortex / cytology Dizocilpine Maleate / pharmacology Dose-Response Relationship, Drug Drug Interactions Embryo, Mammalian Excitatory Amino Acid Agents / pharmacology Fluorescent Antibody Technique / methods Homeostasis / drug effects, physiology* Humans Hydrazones / pharmacology Immunoprecipitation / methods Iron / metabolism* Iron Chelating Agents / pharmacology Iron-Binding Proteins / metabolism Membrane Proteins Mice Mice, Knockout Models, Biological N-Methylaspartate / pharmacology Neurons / drug effects, metabolism Nitric Oxide / physiology* Nitric Oxide Synthase Type I / deficiency, metabolism Protein Binding / drug effects, physiology Rats Reactive Oxygen Species / immunology, metabolism Receptors, GABA-A / metabolism Receptors, N-Methyl-D-Aspartate / physiology* Signal Transduction / drug effects, physiology* Transfection / methods ras Proteins / physiology* |
| Grant Support | |
ID/Acronym/Agency:
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DA000266/DA/NIDA NIH HHS; DA00074/DA/NIDA NIH HHS; K99 MH079614-01/MH/NIMH NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Acbd3 protein, mouse; 0/Adaptor Proteins, Signal Transducing; 0/Aldehydes; 0/Cation Transport Proteins; 0/Excitatory Amino Acid Agents; 0/Hydrazones; 0/Iron Chelating Agents; 0/Iron-Binding Proteins; 0/Membrane Proteins; 0/Reactive Oxygen Species; 0/Receptors, GABA-A; 0/Receptors, N-Methyl-D-Aspartate; 0/salicylaldehyde isonicotinoyl hydrazone; 0/solute carrier family 11- (proton-coupled divalent metal ion transporters), member 2; 10102-43-9/Nitric Oxide; 6384-92-5/N-Methylaspartate; 7439-89-6/Iron; 77086-22-7/Dizocilpine Maleate; EC 1.14.13.39/Nitric Oxide Synthase Type I; EC 3.6.1.-/Rasd1 protein, mouse; EC 3.6.5.2/ras Proteins |
| Comments/Corrections | |
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