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 pro-apoptotic 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.

Acetylation of TUG Protein Promotes the Accumulation of GLUT4 Glucose Transporters in an Insulin-responsive Intracellular Compartment

“…ACBD3 binds proteins present on mitochondria, notably the 18-kDa translocator protein, TSPO, and it recruits protein kinase A regulatory subunit 1␣ to facilitate the import of cholesterol for steroid synthesis (46). In the brain, ACBD3 binds complexes containing the GTPases Dexras1 and Rhes to regulate divalent metal transporters (47,48) and to mediate the neurotoxicity associated with mutated huntingtin proteins, respectively (49). During mitosis, ACBD3 is released into the cytosol and functions together with Numb proteins to specify the developmental fate of daughter cells (22).…”

Dexras1 mediates glucocorticoid-associated adipogenesis and diet-induced obesity

“…We generated Dexras1 knockout mice by deleting whole Dexras1 exons flanked by loxp sites with Cre recombinase (28). Then, Dexras1 mice were backcrossed onto C57BL/6J background for eight generations.…”

Activators of G Protein Signaling Exhibit Broad Functionality and Define a Distinct Core Signaling Triad

“…1). Disruption of the Ric-8A gene, but not that of AGS1, Rhes, or GIV, is embryonic lethal (Cheng et al, 2004;Spano et al, 2004;Tonissoo et al, 2006;Kitamura et al, 2008;Enomoto et al, 2009;Tonissoo et al, 2010;Gabay et al, 2011;Wang et al, 2011;Chen et al, 2013).…”

“…Both AGS1 and Rhes have an extended carboxyl terminus as compared with Ras family proteins, and both proteins interact with G i /G o and regulate G protein signaling (Cismowski et al, , 2000Graham et al, 2002Graham et al, , 2004Takesono et al, 2002;Vargiu et al, 2004;Nguyen and Watts, 2005;Harrison and He, 2011). AGS1 has a range of functional roles, including inhibition of cell growth, N-methyl-D-aspartate receptor signaling, regulation of the circadian rhythm, and regulation of hormone secretion (Fang et al, 2000;Graham et al, 2001;Jaffrey et al, 2002;Takahashi et al, 2003;Cheng et al, 2004;Vaidyanathan et al, 2004;Lellis-Santos et al, 2012;McGrath et al, 2012;Chen et al, 2013;Harrison et al, 2013). Rhes …”