dizocilpine-maleate and salicylaldehyde-isonicotinoyl-hydrazone

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.

Topics: Adaptor Proteins, Signal Transducing; Aldehydes; Animals; Blotting, Western; Cation Transport Proteins; Cells, Cultured; Cerebral Cortex; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Interactions; Embryo, Mammalian; Excitatory Amino Acid Agents; Fluorescent Antibody Technique; Homeostasis; Humans; Hydrazones; Immunoprecipitation; Iron; Iron Chelating Agents; Iron-Binding Proteins; Membrane Proteins; Mice; Mice, Knockout; Models, Biological; N-Methylaspartate; Neurons; Nitric Oxide; Nitric Oxide Synthase Type I; Protein Binding; ras Proteins; Rats; Reactive Oxygen Species; Receptors, GABA-A; Receptors, N-Methyl-D-Aspartate; Signal Transduction; Transfection