Differentiation of substrate and non-substrate inhibitors of transport system xc-:: an obligate exchanger of L-glutamate and L-cystine

被引:129
作者
Patel, SA [1 ]
Warren, BA [1 ]
Rhoderick, JF [1 ]
Bridges, RJ [1 ]
机构
[1] Univ Montana, COBRE, Ctr Struct & Funct Neurosci, Dept Biomed & Pharmaceut Sci, Missoula, MT 59812 USA
关键词
excitatory amino acids; uptake; glutathione; quisqualate; S-4-carboxyphenylglycine; xCT;
D O I
10.1016/j.neuropharm.2003.08.006
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
In addition to the we 11-characterized sodium-dependent excitatory amino acid transporters (EAATs) present in the mammalian CNS, a chloride-dependent, sodium-independent transporter has also been identified that is capable of mediating the uptake of L-alutamate. Named system x(c)(-), this transporter is an obligate exchanger that normally couples the export of intracellular L-glutamate with the import of extracellular L-cystine. Two cell lines that express high levels of system x(c)(-) are used to delineate the pharmacology of the transporter and demonstrate that it is distinct from both the EAATs and EAA ionotropic receptors. Potent competitive inhibitors of system x(c)(-) include: L-homocysteate, ibotenate, L-serine-O-sulphate, (RS)-4-bromohomoibotenate, quisqualate, and (S)-4-carboxyphenyl-lycine. A fluorescent-based assay that allows system x-mediated exchange of L-glutamate and L-cystine to be C C followed in real time is used to assess substrate activity. Interestingly, those compounds that proved to be the most potent competitive inhibitors (e.g. L-quisqualate and 4-S-CPG) also proved to be the least active as substrates, suggesting that distinct structural features may control binding and translocation. Lastly, the finding that a number of system x, inhibitors are also commonly used as probes of excitotoxic pathology (e.g., L-quisqualate, ibotenate and L-homocysteate) raises some interesting questions regarding the mechanisms through which these analogues produce CNS damage. (C) 2003 Elsevier Ltd. All rights reserved.
引用
收藏
页码:273 / 284
页数:12
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