CNS & Neurological Disorders - Drug Targets

(Formerly Current Drug Targets - CNS & Neurological Disorders)

Stephen D. Skaper  
Department of Pharmaceutical and Pharmacological Sciences
University of Padova
Padova
Italy

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Mechanisms of Oxidative Glutamate Toxicity: The Glutamate/Cystine Antiporter System xc¯ as a Neuroprotective Drug Target

Author(s): Philipp Albrecht, Jan Lewerenz, Sonja Dittmer, Rebecca Noack, Pamela Maher, Axel Methner.

Abstract:

The glutamate/cystine antiporter system xc¯ 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 xc¯ 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 xc¯ thus connects the antioxidant defense with neurotransmission and behavior. Disturbances in the function of system xc¯ have been implicated in nerve cell death due to increased extracellular glutamate and reduced intracellular glutathione. In vitro, inhibition of cystine import through system xc¯ 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 xc¯ 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.

Keywords: Oxidative stress, glutathione, glutamate, xCT, EAAT

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Article Details

VOLUME: 9
ISSUE: 3
Year: 2010
Page: [373 - 382]
Pages: 10
DOI: 10.2174/187152710791292567
Price: $58