Journal
ANTIOXIDANTS & REDOX SIGNALING
Volume 18, Issue 5, Pages 522-555Publisher
MARY ANN LIEBERT, INC
DOI: 10.1089/ars.2011.4391
Keywords
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Funding
- Fritz-Thyssen-Stiftung [Az10.08.1.174]
- National Institutes of Health NEI [2R01 EY012830, 2R01 EY014560]
- National Institutes of Health NINDS [NS051445]
- Medical Foundation Queen Elisabeth
- Charcot Foundation
- Alzheimer's Association [IRG-07-58874]
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The antiporter system x(c)(-) imports the amino acid cystine, the oxidized form of cysteine, into cells with a 1: 1 counter-transport of glutamate. It is composed of a light chain, xCT, and a heavy chain, 4F2 heavy chain (4F2hc), and, thus, belongs to the family of heterodimeric amino acid transporters. Cysteine is the rate-limiting substrate for the important antioxidant glutathione (GSH) and, along with cystine, it also forms a key redox couple on its own. Glutamate is a major neurotransmitter in the central nervous system (CNS). By phylogenetic analysis, we show that system x(c)(-) is a rather evolutionarily new amino acid transport system. In addition, we summarize the current knowledge regarding the molecular mechanisms that regulate system x(c)(-) , including the transcriptional regulation of the xCT light chain, posttranscriptional mechanisms, and pharmacological inhibitors of system x(c)(-) . Moreover, the roles of system x(c)(-) in regulating GSH levels, the redox state of the extracellular cystine/cysteine redox couple, and extracellular glutamate levels are discussed. In vitro, glutamate-mediated system x(c)(-) inhibition leads to neuronal cell death, a paradigm called oxidative glutamate toxicity, which has successfully been used to identify neuroprotective compounds. In vivo, xCT has a rather restricted expression pattern with the highest levels in the CNS and parts of the immune system. System x(c)(-) is also present in the eye. Moreover, an elevated expression of xCT has been reported in cancer. We highlight the diverse roles of system x(c)(-) in the regulation of the immune response, in various aspects of cancer and in the eye and the CNS. Antioxid. Redox Signal. 18, 522-555.
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