title: Dexras1, a small GTPase, is required for glutamate-NMDA neurotoxicity.
abstract: Dexras1, a small G-protein localized predominantly to the brain, is transcriptionally upregulated by the synthetic glucocorticoid dexamethasone. It has close homology to the Ras subfamily but differs in that Dexras1 contains an extended 7 kDa C-terminal tail. Previous studies in our laboratory showed that NMDA receptor activation, via NO and Dexras1, physiologically stimulates DMT1, the major iron importer. A membrane-permeable iron chelator substantially reduces NMDA excitotoxicity, suggesting that Dexras1-mediated iron influx plays a crucial role in NMDA/NO-mediated cell death. We here report that iron influx is elicited by nitric oxide but not by other proapoptotic stimuli, such as H₂O₂ or staurosporine. Deletion of Dexras1 in mice attenuates NO-mediated cell death in dissociated primary cortical neurons and retinal ganglion cells in vivo. Thus, Dexras1 appears to mediate NMDA-elicited neurotoxicity via NO and iron influx.
authors: Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors: Yong
authors: Y
authors: Chen
authors: Reas S
authors: RS
authors: Khan
authors: Alyssa
authors: A
authors: Cwanger
authors: Ying
authors: Y
authors: Song
authors: Catherine
authors: C
authors: Steenstra
authors: Sookhee
authors: S
authors: Bang
authors: Jaime H
authors: JH
authors: Cheah
authors: Joshua
authors: J
authors: Dunaief
authors: Kenneth S
authors: KS
authors: Shindler
authors: Solomon H
authors: SH
authors: Snyder
authors: Sangwon F
authors: SF
authors: Kim
mesh_terms: D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects / Q000502:physiology*; D018698:Glutamic Acid / Q000502:physiology / Q000633:toxicity*; D057809:HEK293 Cells; D006801:Humans; D007501:Iron / Q000378:metabolism / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020559:Monomeric GTP-Binding Proteins / Q000172:deficiency / Q000502:physiology; D016202:N-Methylaspartate / Q000502:physiology / Q000633:toxicity*; D009569:Nitric Oxide / Q000502:physiology / Q000633:toxicity; D016716:PC12 Cells; D051381:Rats; D012165:Retinal Ganglion Cells / Q000502:physiology*; D018631:ras Proteins / Q000172:deficiency / Q000502:physiology*
chemical_list: D009569:Nitric Oxide; D018698:Glutamic Acid; D016202:N-Methylaspartate; D007501:Iron; C498511:Rasd1 protein, mouse; D020559:Monomeric GTP-Binding Proteins; D018631:ras Proteins