NMDA receptor-nitric oxide transmission mediates neuronal iron homeostasis via the GTPase Dexras1.
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.
Cheah
Jaime H
JH
Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Kim
Sangwon F
SF
Hester
Lynda D
LD
Clancy
Kathleen W
KW
Patterson
Stanley E
SE
Papadopoulos
Vassilios
V
Snyder
Solomon H
SH
D048868:Adaptor Proteins, Signal Transducing; D000447:Aldehydes / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western / Q000379:methods; D027682:Cation Transport Proteins / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004622:Embryo, Mammalian; D018683:Excitatory Amino Acid Agents / Q000494:pharmacology; D005455:Fluorescent Antibody Technique / Q000379:methods; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D006835:Hydrazones / Q000494:pharmacology; D047468:Immunoprecipitation / Q000379:methods; D007501:Iron / Q000378:metabolism*; D007502:Iron Chelating Agents / Q000494:pharmacology; D033862:Iron-Binding Proteins / Q000378:metabolism; D008565:Membrane Proteins; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009569:Nitric Oxide / Q000502:physiology*; D052248:Nitric Oxide Synthase Type I / Q000172:deficiency / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017382:Reactive Oxygen Species / Q000276:immunology / Q000378:metabolism; D011963:Receptors, GABA-A / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014162:Transfection / Q000379:methods; D018631:ras Proteins / Q000502:physiology*; D000099236:Solute Carrier Family 11, Member 2
D048868:Adaptor Proteins, Signal Transducing; D000447:Aldehydes; D027682:Cation Transport Proteins; D016291:Dizocilpine Maleate; D018683:Excitatory Amino Acid Agents; D006835:Hydrazones; D007501:Iron; D007502:Iron Chelating Agents; D033862:Iron-Binding Proteins; D008565:Membrane Proteins; D016202:N-Methylaspartate; D009569:Nitric Oxide; D052248:Nitric Oxide Synthase Type I; D017382:Reactive Oxygen Species; D011963:Receptors, GABA-A; D016194:Receptors, N-Methyl-D-Aspartate; D018631:ras Proteins; D000099236:Solute Carrier Family 11, Member 2; C486730:Acbd3 protein, mouse; C413684:salicylaldehyde isonicotinoyl hydrazone; C498511:Rasd1 protein, mouse