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PMID: 16908409 Published · ppublish English Comparative Study Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

NMDA receptor-nitric oxide transmission mediates neuronal iron homeostasis via the GTPase Dexras1.

Neuron ·Vol. 51 ·No. 4 ·2006-08-17 ·Pages 431-40

Cheah JH, Kim SF, Hester LD, Clancy KW, Patterson SE, Papadopoulos V, Snyder SH

Abstract

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.

MeSH Terms
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
Chemicals
Acbd3 protein, mouse Adaptor Proteins, Signal Transducing Aldehydes Cation Transport Proteins Excitatory Amino Acid Agents Hydrazones Iron Chelating Agents Iron-Binding Proteins Membrane Proteins Reactive Oxygen Species Receptors, GABA-A Receptors, N-Methyl-D-Aspartate salicylaldehyde isonicotinoyl hydrazone solute carrier family 11- (proton-coupled divalent metal ion transporters), member 2 Nitric Oxide N-Methylaspartate Dizocilpine Maleate Iron Nitric Oxide Synthase Type I Rasd1 protein, mouse ras Proteins
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Cheah Jaime H
Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Kim Sangwon F
Hester Lynda D
Clancy Kathleen W
Patterson Stanley E
Papadopoulos Vassilios
Snyder Solomon H
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Article Info
Journal
Neuron
Abbr.
Neuron
ISSN
0896-6273
DOI
10.1016/j.neuron.2006.07.011
Published
2006-08-17
Pages
431-40
Language
English
Region
United States
NLM ID
8809320
PMCID
PMC3150500
Subset
IM
Grants
NIDA NIH HHS · DA00074 · United States
NIMH NIH HHS · K99 MH079614-01 · United States
NIDA NIH HHS · P50 DA000266 · United States
NIDA NIH HHS · K05 DA000074 · United States
NIMH NIH HHS · K99 MH079614 · United States
NIDA NIH HHS · DA000266 · United States
External Links
PubMed source DOI: 10.1016/j.neuron.2006.07.011 PMC Full Text View journal details
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