Role of glutamate transporters in the regulation of glutathione levels in human macrophages.
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 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 system) and overcome competition for the use of cystine transporters. We now show that macrophages take up cystine through the x 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.
Rimaniol
A C
AC
Service de Neurovirologie, CEA, DSV/DRM, Centre de Recherches du Service de Santé des Armées, Ecole Pratique des Hautes Etudes, Institut Paris Sud sur les Cytokines, 92265 Fontenay-aux-Roses cedex, France. rimaniol@dsvidf.cea.fr
Mialocq
P
P
Clayette
P
P
Dormont
D
D
Gras
G
G
D027182:Amino Acid Transport System y+; D002352:Carrier Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D003553:Cystine / Q000378:metabolism / Q000494:pharmacology; D027341:Excitatory Amino Acid Transporter 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D027342:Excitatory Amino Acid Transporter 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism* / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D008264:Macrophages / Q000378:metabolism*; D008954:Models, Biological
D027182:Amino Acid Transport System y+; D002352:Carrier Proteins; D027341:Excitatory Amino Acid Transporter 1; D027342:Excitatory Amino Acid Transporter 2; C118895:SLC7A11 protein, human; D018698:Glutamic Acid; D003553:Cystine; D005978:Glutathione