System x_c⁻ is a heterodimeric amino acid antiporter that, in the central nervous system, is best known for linking the import of L-cystine (CySS) with the export of L-glutamate for the production and maintenance of cellular glutathione (GSH) and extracellular glutamate levels, respectively. Yet, mice that are null for system x_c⁻ are healthy, fertile, and, morphologically, their brains are grossly normal. This suggests other glutamate and/or cyst(e)ine transport mechanisms may be upregulated in compensation. To test this, we measured the plasma membrane expression of Excitatory Amino Acid Transporters (EAATs) 1–3, the Alanine-Serine-Cysteine-Transporter (ASCT) 1, the sodium-coupled neutral amino acid transporter (SNAT) 3 and the L Amino Acid Transporter (LAT) 2 in striatum, hippocampus and cortex of male and female mice using Western Blot analysis. Present results demonstrate brain region and transporter-specific changes occurs in female system x_c⁻ null mice with increased expression of EAAT1 and ASCT1 occurring in the striatum and cortex, respectively, and decreased SNAT 3 expression in cortex. In male system x_c⁻ null brain, only SNAT3 was altered significantly - increasing in the cortex, but decreasing in the striatum. Total levels of GSH and CyS were similar to that found in age and sex-matched littermate control mice, however, reductions in the ratio of reduced to oxidized GSH (GSH/GSSG) — a hallmark of oxidative stress — were found in all three brain regions in female system x_c⁻ null mice, whereas this occurred exclusively in the striatum of males. Protein levels of Superoxide dismutase (SOD) 1 were reduced, whereas SOD2 was enhanced in the hippocampus of male x_c⁻ null mice only. Finally, striatal vulnerability to 3-nitropropionic acid (3-NP)-mediated oxidative stress in either sex showed no genotype difference, although 3-NP was more toxic to female mice of either genotype, as evidenced by an increase in moribundity as compared to males.

System x _c ^-是一种异二聚体氨基酸反向转运蛋白，在中枢神经系统中，最著名的是将 L-胱氨酸 (CySS) 的输入与 L-谷氨酸的输出联系起来，以产生和维持细胞谷胱甘肽 (GSH)和细胞外谷氨酸水平，分别。然而，对于系统 x _c为空的小鼠^-他们是健康的、有生育能力的，而且在形态上，他们的大脑非常正常。这表明其他谷氨酸和/或胱氨酸转运机制可能在补偿中上调。为了测试这一点，我们测量了兴奋性氨基酸转运蛋白 (EAAT) 1-3、丙氨酸-丝氨酸-半胱氨酸转运蛋白 (ASCT) 1、钠偶联中性氨基酸转运蛋白 (SNAT) 3 和 L使用蛋白质印迹分析的雄性和雌性小鼠的纹状体、海马体和皮质中的氨基酸转运蛋白 (LAT) 2。目前的结果表明，脑区域和转运蛋白特异性变化发生在雌性系统 x _c ^- null 小鼠中，EAAT1 和 ASCT1 的表达分别增加，分别出现在纹状体和皮质中，而皮质中的 SNAT 3 表达降低。在男性系统 x_c ^-空脑，只有 SNAT3 显着改变 - 在皮质中增加，但在纹状体中减少。GSH 和 CyS 的总水平与在年龄和性别匹配的同窝对照小鼠中发现的相似，但是，在所有三个大脑中都发现还原型与氧化型 GSH 的比率（GSH/GSSG）——氧化应激的标志——降低雌性系统 x _c ^-空小鼠中的区域，而这仅发生在雄性的纹状体中。超氧化物歧化酶 (SOD) 1 的蛋白质水平降低，而 SOD2 在雄性 x _c的海马中增加^-仅空小鼠。最后，纹状体对 3-硝基丙酸 (3-NP) 介导的氧化应激的易感性在任何一种性别中都没有显示出基因型差异，尽管 3-NP 对任一基因型的雌性小鼠的毒性更大，这通过与男性。