期刊
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY
卷 281, 期 6, 页码 C1964-C1970出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpcell.2001.281.6.C1964
关键词
cystine; glutamate/cystine antiporter; oxidative stress; glutamine
Cysteine is the limiting precursor for glutathione synthesis. Because of its low bioavailability, cysteine is generally produced from cystine, which may be taken up through two different transporters. The cystine/glutamate antiporter (x(C)(-) system) transports extracellular cystine in exchange for intracellular glutamate. The X-AG transport system takes up extracellular cystine, glutamate, and aspartate. Both are sensitive to competition between cystine and glutamate, and excess extracellular glutamate thus inhibits glutathione synthesis, a nonexcitotoxic mechanism for glutamate toxicity. We demonstrated previously that human macrophages express the glutamate transporters excitatory amino acid transporter (EAAT)1 and EAAT2 (which do not transport cystine, X-AG(-) system) and overcome competition for the use of cystine transporters. We now show that macrophages take up cystine through the x(C)(-) and not the X-AG system. We also found that glutamate, although competing with cystine uptake, dose-dependently increases glutathione synthesis. We used inhibitors to demonstrate that this increase is mediated by EAATs. EAAT expression in macrophages thus leads to glutamate-dependent enhancement of glutathione synthesis by providing intracellular glutamate for direct insertion in glutathione and also for fueling the intracellular pool of glutamate and trans-stimulating the cystine/glutamate antiporter.
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