Publication in detail

The Journal of neuroscience : the official journal of the Society for Neuroscience 2013 Feb 20;33(8):3582-7. doi: 10.1523/JNEUROSCI.1497-12.2013.

Dexras1, a Small GTPase, Is Required for Glutamate-NMDA Neurotoxicity.

Chen, Y; Khan, RS; Cwanger, A; Song, Y; Steenstra, C; Bang, S; Cheah, JH; Dunaief, J; Shindler, KS; Snyder, SH; Kim, SF

Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.

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 H(2)O(2) 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.

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