TY - JOUR
T1 - Dexras1, a small GTPase, is required for glutamate-NMDA neurotoxicity
AU - Chen, Yong
AU - Khan, Reas S.
AU - Cwanger, Alyssa
AU - Song, Ying
AU - Steenstra, Catherine
AU - Bang, Sookhee
AU - Cheah, Jaime H.
AU - Dunaief, Joshua
AU - Shindler, Kenneth S.
AU - Snyder, Solomon H.
AU - Kim, Sangwon F.
PY - 2013/2/20
Y1 - 2013/2/20
N2 - 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.
AB - 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.
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U2 - 10.1523/JNEUROSCI.1497-12.2013
DO - 10.1523/JNEUROSCI.1497-12.2013
M3 - Article
C2 - 23426685
AN - SCOPUS:84874218109
VL - 33
SP - 3582
EP - 3587
JO - Journal of Neuroscience
JF - Journal of Neuroscience
SN - 0270-6474
IS - 8
ER -