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Main path and byways: non‐vesicular glutamate release by system x c − as an important modifier of glutamatergic neurotransmission
Author(s) -
Massie Ann,
Boillée Séverine,
Hewett Sandra,
Knackstedt Lori,
Lewerenz Jan
Publication year - 2015
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.13348
Subject(s) - glutamatergic , neurotransmission , glutamate receptor , neuroscience , chemistry , path (computing) , biophysics , biology , biochemistry , computer science , receptor , programming language
System x c − 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 x c − can regulate the antioxidant capacity of cells. Moreover, in several brain regions, system x c − 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 x c − , is enhanced by the presence of reactive oxygen species and inflammatory cytokines, system x c − could be involved in toxic extracellular glutamate release in neurological disorders that are associated with increased oxidative stress and neuroinflammation. System x c − 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 x c − in the CNS. In this review, we highlight novel achievements and insights covering the regulation of system x c − as well as its involvement in emotional behavior, cognition, addiction, neurological disorders and glioblastomas, acquired in the past few years.System x c − constitutes an important source of extrasynaptic glutamate in the brain. By modulating the tone of extrasynaptic metabotropic or ionotropic glutamate receptors, it affects excitatory neurotransmission, the threshold for overexcitation and excitotoxicity and, as a consequence, behavior. This review describes the current knowledge of how system x c − is regulated and involved in physiological as well as pathophysiological brain functioning.