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

Abstract

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 (Pharmacol. Rev. 64, 2012, 780; Antioxid. Redox Signal. 18, 2013, 522), approached from a different perspective, have recently been published on the functions of system xc- in the CNS. 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.