Thinking Outside the Cleft to Understand Synaptic Activity: Contribution of the Cystine-Glutamate Antiporter (System xc) to Normal and Pathological Glutamatergic Signaling

Document Type




Format of Original

23 p.

Publication Date



American Society for Pharmacology and Experimental Therapeutics

Source Publication

Pharmacological Reviews

Source ISSN


Original Item ID

doi: 10.1124/pr.110.003889; PubMed Central: PMCID 3400835


System xc represents an intriguing target in attempts to understand the pathological states of the central nervous system. Also called a cystine-glutamate antiporter, system xc typically functions by exchanging one molecule of extracellular cystine for one molecule of intracellular glutamate. Nonvesicular glutamate released during cystine-glutamate exchange activates extrasynaptic glutamate receptors in a manner that shapes synaptic activity and plasticity. These findings contribute to the intriguing possibility that extracellular glutamate is regulated by a complex network of release and reuptake mechanisms, many of which are unique to glutamate and rarely depicted in models of excitatory signaling. Because system xc is often expressed on non-neuronal cells, the study of cystine-glutamate exchange may advance the emerging viewpoint that glia are active contributors to information processing in the brain. It is noteworthy that system xc is at the interface between excitatory signaling and oxidative stress, because the uptake of cystine that results from cystine-glutamate exchange is critical in maintaining the levels of glutathione, a critical antioxidant. As a result of these dual functions, system xc has been implicated in a wide array of central nervous system diseases ranging from addiction to neurodegenerative disorders to schizophrenia. In the current review, we briefly discuss the major cellular components that regulate glutamate homeostasis, including glutamate release by system xc. This is followed by an in-depth discussion of system xc as it relates to glutamate release, cystine transport, and glutathione synthesis. Finally, the role of system xc is surveyed across a number of psychiatric and neurodegenerative disorders.


Pharmacological Reviews, Vol. 64, No. 3 (July 2012): 780-802. DOI.