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The cystine/glutamate antiporter system xc- in health and disease: from molecular mechanisms to novel therapeutic opportunities

Tijdschriftbijdrage - Tijdschriftartikel

The antiporter system xc- 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 xc- is a rather evolutionarily new amino acid transport system. In addition, we summarize the current knowledge regarding the molecular mechanisms that regulate system xc
- , including the transcriptional regulation of the xCT light chain, posttranscriptional mechanisms, and pharmacological inhibitors of system xc- . Moreover, the roles of system xc- 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 xc- 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 xc- is also present in the eye. Moreover, an elevated expression of xCT has been reported in cancer. We highlight the diverse roles of system xc- in the regulation of the immune response, in various aspects of cancer and in the eye and the CNS.
Tijdschrift: Antioxid Redox Signal
ISSN: 1523-0864
Issue: 5
Volume: 18
Pagina's: 522-555
Jaar van publicatie:2013
Trefwoorden:system xc-, glutamate, cystine
  • ORCID: /0000-0003-2140-0751/work/62005008
  • ORCID: /0000-0002-8418-5879/work/61335657
  • Scopus Id: 84872191631