Main path and byways: non-vesicular glutamate release by system xc(-) as an important modifier of glutamatergic neurotransmission.
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. System xc(-) 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 xc(-) is regulated and involved in physiological as well as pathophysiological brain functioning.
Department of Pharmaceutical Biotechnology and Molecular Biology, Center for Neurosciences, Vrije Universiteit Brussel, Brussels, Belgium.
Ann
A
Massie
Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, Paris, France.
Séverine
S
Boillée
Department of Biology, Program in Neuroscience, Syracuse University, Syracuse, New York, USA.
Sandra
S
Hewett
Psychology Department, University of Florida, Gainesville, Florida, USA.
Lori
L
Knackstedt
Department of Neurology, Ulm University, Oberer Eselsberg 45, Ulm, Germany.
Jan
J
Lewerenz
D000818:Animals; D001921:Brain / Q000378:metabolism*; D001932:Brain Neoplasms / Q000378:metabolism*; D005909:Glioblastoma / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism*; D006801:Humans; D018384:Oxidative Stress / Q000502:physiology; D009435:Synaptic Transmission / Q000502:physiology*
D018698:Glutamic Acid
addiction; emotional and cognitive behavior; glioblastoma; glutamate; neurological disorders; system xc−