Dexras1, a small GTPase, is required for glutamate-NMDA neurotoxicity.

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.

Striatum specific protein, Rhes regulates AKT pathway.

The Rhes/RASD2 GTPase complex is involved in dopamine D1/D2 receptor-mediated signaling and behavior. This GTP binding protein belongs to the RAS superfamily, along with Dexras1/RASD1, and is primarily expressed in the striatum. RASDs differ from typical small GTPases as they have an extended C-terminal tail of roughly 7 kDa. Previously, it has been shown that dopamine depletion reduces Rhes mRNA expression in the brain. Here we show that Rhes interacts with p85, the regulatory subunit of PI3K. Specifically, the C-terminal unique tail region of Rhes is responsible for this interaction. The interaction between p85 and the C-terminal region of Rhes is enhanced upon growth factor treatment in vitro, while AKT translocation to the membrane is facilitated in the presence of Rhes or the Rhes-p85 complex. These findings suggest that Rhes is a novel striatal regulator of the AKT-mediated pathway in the striatum.