The Cystine/Glutamate Antiporter System x_c⁻in Health and Disease: From Molecular Mechanisms to Novel Therapeutic Opportunities

Abstract

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.

Inflammation, Glutamate, and Glia: A Trio of Trouble in Mood Disorders

“…Nevertheless, there are several important non-vesicular (non-exocytotic) mechanisms responsible for glutamate release in pathological contexts (Malarkey and Parpura, 2008;Zhou and Danbolt, 2014) including: (1) release through anion channels (Wang et al, 2013a); (2) reverse efflux through EAATs (Ye and Sontheimer, 1996), (3) release by xC transporters as part of the cystine-glutamate exchange process (Lewerenz et al, 2013), (4) astrocytic vesicular glutamate release during gliotransmission (Petrelli and Bezzi, 2016) and release through hemi-channels on astrocytes and microglia (Malarkey and Parpura, 2008). A detailed review of the functioning of these release mechanisms is beyond the scope of this review, and the reader is directed elsewhere (Dantzer and Walker, 2014;Malarkey and Parpura, 2008;Najjar et al, 2013;Tilleux and Hermans, 2007).…”

“…Once thought to be exclusively astrocytic in location, now xC-transporters are known to be located on other glial cells including microglia (Lewerenz et al, 2013;Lewerenz and Maher, 2015). As described earlier, the xC-system exchanges cystine for glutamate in a 1 : 1 ratio where glutamate is extruded in exchange for intake of cystine, which is used for the synthesis of glutathione (GSH).…”

“…As described earlier, the xC-system exchanges cystine for glutamate in a 1 : 1 ratio where glutamate is extruded in exchange for intake of cystine, which is used for the synthesis of glutathione (GSH). GSH is the most abundant anti-oxidant molecule in the brain and its absence is usually fatal (Lewerenz et al, 2013;Lewerenz and Maher, 2015). Although in vitro functional ablation of the xC-system leads to fatal oxidative stress from depletion of GSH, in vivo genetic deletion of the system does not lead to oxidative stress or death, possibly due to GSH supplies from alternate cellular systems (Lewerenz et al, 2013;Lewerenz and Maher, 2015).…”

“…GSH is the most abundant anti-oxidant molecule in the brain and its absence is usually fatal (Lewerenz et al, 2013;Lewerenz and Maher, 2015). Although in vitro functional ablation of the xC-system leads to fatal oxidative stress from depletion of GSH, in vivo genetic deletion of the system does not lead to oxidative stress or death, possibly due to GSH supplies from alternate cellular systems (Lewerenz et al, 2013;Lewerenz and Maher, 2015). Although the source of oxidative stress has been assumed to be due to immune stimulation, states of intense neural activity such as stress can also increase demand for GSH-which is met through an NMDA-mediated hyperactivation of GSH biosynthesis within in the neurons (Baxter et al, 2015;Nathan and Cunningham-Bussel, 2013).…”

“…The glutamate that is extruded by the xC-system further adds to the extrasynaptic glutamatergic load. In several brain regions, the xC-system is a major source of both intracellular GSH and extracellular glutamate, and its enhanced transcription following induction can have widely varying effects ranging from intracellular protective effects to toxic increases in extracellular glutamate (Lewerenz et al, 2013). Excessive extracellular glutamate can bind to the xC-transporters and lead to their toxic paralysis resulting in GSH depletion and cell death-a process referred to as 'oxidative glutamate toxicity'-in contrast to excitotoxic glutamate toxicity resulting from overstimulation of ionotropic receptors (Lewerenz et al, 2013).…”