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- W2318884329 abstract "Oxidative stress plays a role in many neurological diseases such as Alzheimer's and Parkinson's disease, or stroke. Oxidative glutamate toxicity in the mouse hippocampal cell line HT22 serves as a model system for neuronal death in response to oxidative stress, in which excess extracellular glutamate inhibits the import of cystine via the glutamate/cystine antiporter system Xc-. Cystine is a crucial constituent for the synthesis of the antioxidant glutathione (GSH), and thus induces intracellular GSH depletion, followed by a rise in reactive oxygen species and programmed cell death. To characterize pathways of resistance against oxidative stress, we selected HT22 cells resistant to glutamate toxicity. In these cells, we observed an increase in GSH-levels and a prominently decreased GSH-depletion in response to glutamate compared to wildtype HT22 cells. This phenotype was associated with a 8-fold increase in expression of the specific xCT subunit of the system Xc- and a more than 10-fold increase in its activity. As glutamate normally blocks cystine import via the system Xc-, we quantified glutamate-mediated cystine uptake inhibition, which proofed to be shifted to higher glutamate concentrations. We hypothesized that a concomitant increase in glutamate import might explain this phenomenon, which might be mediated by excitatory amino acid transporters (EAAT). This assumption was supported the observation that the EAAT-blocking agent l-trans-pyrrolidine-2,4-dicarboxylic acid exacerbates glutamate toxicity in glutamate-resistant cells. Thus, we studied the cooperative action of EAATs and xCT by transiently overexpressing xCT and the neuronal glutamate transporter EAAT3 or both in glutamate-sensitive HT22 cells. This clearly showed that both increase GSH levels and confer protection against glutamate and oxidative stress induced by hydrogen peroxide. Supporting the hypothesis of an cooperative effect of EAATs and xCT, co-transfection of both yielded a more than additive effect under higher glutamate concentrations and prolonged exposure times. These findings suggest that cooperative glutamate import by EAAT glutamate transporters and subsequent re-export coupled with cystine-import by xCT might be a powerful mechanism to maintain neuronal GSH homeostasis under stressful conditions to prevent neuronal cell death." @default.
- W2318884329 created "2016-06-24" @default.
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- W2318884329 date "2004-01-01" @default.
- W2318884329 modified "2023-09-25" @default.
- W2318884329 title "Excitatory amino acid transporter 3 and the glutamate/cystine antiporter system Xc- cooperatively protect neuronal HT22 cells from oxidative glutamate toxicity" @default.
- W2318884329 doi "https://doi.org/10.1055/s-2004-833373" @default.
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