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

Neuropharmacology. 2004 Feb;46(2):273-84. doi: 10.1016/j.neuropharm.2003.08.006.


In addition to the well-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-glutamate. 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-carboxyphenylglycine. A fluorescent-based assay that allows system x(c)(-)-mediated exchange of L-glutamate and L-cystine to be 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(c)(-) 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.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Transport System y+*
  • Animals
  • Carrier Proteins / metabolism*
  • Cell Line, Tumor
  • Cystine / chemistry
  • Cystine / pharmacokinetics*
  • Glutamic Acid / chemistry
  • Glutamic Acid / pharmacokinetics*
  • Humans
  • Rats
  • Substrate Specificity / physiology


  • Amino Acid Transport System y+
  • Carrier Proteins
  • SLC7A11 protein, human
  • Glutamic Acid
  • Cystine