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  • The cystine/glutamate antiporter system x(c)(-) in health and disease: from molecular mechanisms to novel therapeutic opportunities.

The cystine/glutamate antiporter system x(c)(-) in health and disease: from molecular mechanisms to novel therapeutic opportunities.

Antioxidants & redox signaling (2012-06-07)
Jan Lewerenz, Sandra J Hewett, Ying Huang, Maria Lambros, Peter W Gout, Peter W Kalivas, Ann Massie, Ilse Smolders, Axel Methner, Mathias Pergande, Sylvia B Smith, Vadivel Ganapathy, Pamela Maher
RESUMO

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.

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Sigma-Aldrich
L-Cystine, ≥98% (TLC), crystalline
Sigma-Aldrich
L-Cystine, from non-animal source, meets EP testing specifications, suitable for cell culture, 98.5-101.0%
Supelco
L-Cystine, certified reference material, TraceCERT®
Sigma-Aldrich
L-Cystine, produced by Wacker Chemie AG, Burghausen, Germany, ≥98.5%
Sigma-Aldrich
L-Cystine, ≥99.7% (TLC)
SAFC
L-Cystine
Supelco
L-Cystine, Pharmaceutical Secondary Standard; Certified Reference Material
Cystine, European Pharmacopoeia (EP) Reference Standard
SAFC
L-Cystine