Journal
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY
Volume 281, Issue 6, Pages C1964-C1970Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpcell.2001.281.6.C1964
Keywords
cystine; glutamate/cystine antiporter; oxidative stress; glutamine
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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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