System x_c^‐ cystine/glutamate antiporter: an update on molecular pharmacology and roles within the CNS

Abstract

System xc-is an amino acid antiporter that typically mediates the exchange of extracellular L-cystine and intracellular L-glutamate across the cellular plasma membrane. Studied in a variety of cell types, the import of L-cystine through this transporter is critical to glutathione production and oxidative protection. The exchange-mediated export of L-glutamate takes on added significance within the CNS, as it represents a non-vesicular route of release through which this excitatory neurotransmitter can participate in either neuronal signalling or excitotoxic pathology. When both the import of L-cystine and the export of L-glutamate are taken into consideration, system xc -has now been linked to a wide range of CNS functions, including oxidative protection, the operation of the blood-brain barrier, neurotransmitter release, synaptic organization, viral pathology, drug addiction, chemosensitivity and chemoresistance, and brain tumour growth. The ability to selectively manipulate system xc -, delineate its function, probe its structure and evaluate it as a therapeutic target is closely linked to understanding its pharmacology and the subsequent development of selective inhibitors and substrates. Towards that goal, this review will examine the current status of our understanding of system xc -pharmacology and the structure-activity relationships that have guided the development of an initial pharmacophore model, including the presence of lipophilic domains adjacent to the substrate binding site. A special emphasis is placed on the roles of system xc -within the CNS, as it is these actions that are among the most exciting as potential long-range therapeutic targets. Abbreviations4-S-CPG (S)-4-carboxyphenyglycine; 4-S-SPG, sulphonic acid phenylglycine; ACPA, amino-3-carboxy-5-methyl isoxazole propionic acid; trans-ACPD,1-aminocyclopentane-trans-1,3-dicarboxylic acid; ApcT, amino acid polyamine organo-cation transporter; ARE, antioxidant response element; ASC, alanine-serine-cysteine uptake systems; b-L-ODAP, L-b-N-oxalyl-L-a,b-diaminopropionate; BSO, buthionine sulphoximine; CPPG (R,S)-4-[4′-carboxyphenyl]-phenylglycine; dbcAMP, dibutyryl cyclic AMP; EAA, excitatory amino acid; EAAT, excitatory amino acid transporter; GSH, glutathione; HAT, heteromeric amino acid transporter family; iGluR, ionotropic glutamate receptor; KA, kainate; L-CysH, L-cysteine; L-Cys2, L-cystine; L-trans-2,4-PDC, L-trans-2,4-pyrrolidine dicarboxylate; mGluR, metabotropic glutamate receptor; NAC, N-acetyl-cysteine; NACPA, S-2-naphthyl-ethyl-ACPA; NEIH, 5-naphthylethyl isoxazole-4-(2,4-dinitrophenol)hydrazonedinitrophenol; Nrf2, nuclear factor erythroid-2-related factor; QA, quisqualate; ROS, reactive oxygen species; SAR, structure-activity-relationship; SLC, solute carrier gene families, SSZ, sulphasalazine, ) is an amino acid antiporter that typically mediates the exchange of extracellular L-cystine (L-Cys2) and intracellular L-glutamate (L-Glu) across the cellular plasma membrane. Initial characterizations of this transporter most often focus...

Glioblastoma cells induce differential glutamatergic gene expressions in human tumor-associated microglia/macrophages and monocyte-derived macrophages

“…34 While the other tested glutamatergic genes showed increased levels in fTAMs, fTAMs exhibited a near-significant decrease in xCT gene expression compared to hMGs. The decrease in xCT gene expression was observed to be statistically significant in MDMs after co-culture with glioblastoma cells compared to MDMs after co-culture with NHA.…”

Extrasynaptic glutamate release through cystine/glutamate antiporter contributes to ischemic damage

“…We further assessed the effect of CPG on extracellular direct-current (DC) field potentials (46) and showed that CPG significantly reduced the ΔV o amplitude after OGD ( Figure 3C). Because CPG is also a competitive inhibitor of group I metabotropic glutamate receptors (mGluR 1 ) (47), we also tested sulfasalazine (SAS; 250 μM), another nonsubstrate inhibitor of the cystine/glutamate antiporter (44,45) with no affinity for glutamate receptors, and obtained a similar attenuation of the AD current ( Figure 3, A and B). In contrast, glutamate, which is released into the extracellular space, could be deleterious to neuronal cells and other tissues that are susceptible to excitotoxic damage.…”

“…To analyze the possible contribution of the cystine/glutamate antiporter to glutamate release during OGD, we applied S-4-carboxyphenylglycine (CPG; 250 μM) ( Figure 3A), a nonsubstrate inhibitor of the antiporter (refs. 44,45, and see also Supplemental Figure 3). We found that although CPG did not change latency to AD, it significantly reduced its amplitude ( Figure 3, A and B).…”

Hydrogen sulfide as an oxygen sensor

“…System X c -: System X c -is a cystine/glutamate antiporter that transports l-cystine into cells in exchange for glutamate (12). While system X c -is generally regarded as a mechanism to ultimately increase intracellular l-cysteine for subsequent glutathione synthesis and antioxidant protection, it could also provide a substrate for H 2 S formation.…”