Main path and byways: non-vesicular glutamate release by system xc (-) as an important modifier of glutamatergic neurotransmission

Ann Massie, Severine Boillee, Sandra Hewett, Lori Knackstedt, Jan Lewerenz

Research output: Contribution to journalArticle

61 Citations (Scopus)


System xc (-) is a cystine/glutamate antiporter that exchanges extracellular cystine for intracellular glutamate. Cystine is intracellularly reduced to cysteine, a building block of GSH. As such, system xc (-) can regulate the antioxidant capacity of cells. Moreover, in several brain regions, system xc (-) is the major source of extracellular glutamate. As such this antiporter is able to fulfill key physiological functions in the CNS, while evidence indicates it also plays a role in certain brain pathologies. Since the transcription of xCT, the specific subunit of system xc (-) , is enhanced by the presence of reactive oxygen species and inflammatory cytokines, system xc (-) could be involved in toxic extracellular glutamate release in neurological disorders that are associated with increased oxidative stress and neuroinflammation. System xc (-) has also been reported to contribute to the invasiveness of brain tumors and, as a source of extracellular glutamate, could participate in the induction of peritumoral seizures. Two independent reviews (Lewerenz et al. 2013, Bridges et al. 2012), approached from a different perspective, have recently been published on the functions of system xc (-) in the central nervous system. In this review, we highlight novel achievements and insights covering the regulation of system xc (-) as well as its involvement in emotional behavior, cognition, addiction, neurological disorders and glioblastomas, acquired in the past few years. This article is protected by copyright. All rights reserved.

Original languageEnglish
Pages (from-to)1062-1079
Number of pages18
JournalJournal of Neurochemistry
Issue number6
Publication statusPublished - 2015

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