The cystine/glutamate antiporter system x(c)(-) in health and disease: from molecular mechanisms to novel therapeutic opportunities.
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.
Department of Neurology, University of Ulm, Ulm, Germany. jan.lewerenz@googlemail.com
Jan
J
Lewerenz
Sandra J
SJ
Hewett
Ying
Y
Huang
Maria
M
Lambros
Peter W
PW
Gout
Peter W
PW
Kalivas
Ann
A
Massie
Ilse
I
Smolders
Axel
A
Methner
Mathias
M
Pergande
Sylvia B
SB
Smith
Vadivel
V
Ganapathy
Pamela
P
Maher
D026905:Amino Acid Transport Systems / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D003553:Cystine / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism*; D006801:Humans; D010084:Oxidation-Reduction; D010802:Phylogeny
D026905:Amino Acid Transport Systems; D018698:Glutamic Acid; D003553:Cystine