title: Mechanisms of oxidative glutamate toxicity: the glutamate/cystine antiporter system xc- as a neuroprotective drug target.
abstract: The glutamate/cystine antiporter system x(c)- transports cystine into cells in exchange for the important neurotransmitter glutamate at a ratio of 1:1. It is composed of a specific light chain, xCT, and a heavy chain, 4F2, linked by a disulfide bridge. Both subunits are localized prominently in the mouse and human brain especially in border areas between the brain and periphery including vascular endothelial cells, ependymal cells, choroid plexus, and leptomeninges. Glutamate exported by system x(c)- is largely responsible for the extracellular glutamate concentration in the brain, whereas the imported cystine is required for the synthesis of the major endogenous antioxidant, glutathione. System x(c)- thus connects the antioxidant defense with neurotransmission and behavior. Disturbances in the function of system x(c)- have been implicated in nerve cell death due to increased extracellular glutamate and reduced intracellular glutathione. In vitro, inhibition of cystine import through system x(c)- leads to cell death by a mechanism called oxidative glutamate toxicity or oxytosis, which includes depletion of intracellular glutathione, activation of 12-lipoxygenase, accumulation of intracellular peroxides, and the activation of a cyclic guanosine monophosphate (cGMP)-dependent calcium channel towards the end of the death cascade. Cell death caused by oxytosis is distinct from classical apoptosis. In this contribution, we discuss the function of system x(c)- in vitro and in vivo, the role of xCT as an important but due to its dual role probably ambivalent drug target, and the relevance of oxytosis as an in vitro assay for the identification of novel neuroprotective proteins and signaling pathways.
authors.affiliation: Department of Neurology, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Albrecht
authors.forename: Jan
authors.initials: J
authors.lastname: Lewerenz
authors.forename: Sonja
authors.initials: S
authors.lastname: Dittmer
authors.forename: Rebecca
authors.initials: R
authors.lastname: Noack
authors.forename: Pamela
authors.initials: P
authors.lastname: Maher
authors.forename: Axel
authors.initials: A
authors.lastname: Methner
mesh_terms: D027182:Amino Acid Transport System y+ / Q000378:metabolism* / Q000502:physiology; D000818:Animals; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D003553:Cystine / Q000378:metabolism*; D016503:Drug Delivery Systems / Q000379:methods*; D018698:Glutamic Acid / Q000009:adverse effects / Q000378:metabolism / Q000633:toxicity*; D006801:Humans; D051379:Mice; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism* / Q000502:physiology; D018696:Neuroprotective Agents / Q000378:metabolism* / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D027182:Amino Acid Transport System y+; D018696:Neuroprotective Agents; C118895:SLC7A11 protein, human; D018698:Glutamic Acid; D003553:Cystine