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

Authors

Richard Bridges, University of Montana - Missoula
Victoria Lutgen, Marquette University
Doug Lobner, Marquette University
David Baker, Marquette UniversityFollow

Document Type

Article

Language

eng

Publication Date

7-2012

Publisher

American Society for Pharmacology and Experimental Therapeutics

Source Publication

Pharmacological Reviews

Source ISSN

0031-6997

Original Item ID

DOI: 10.1124/pr.110.003889

Abstract

System x_c⁻ represents an intriguing target in attempts to understand the pathological states of the central nervous system. Also called a cystine-glutamate antiporter, system x_c⁻ 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 x_c⁻ 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 x_c⁻ 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 x_c⁻ 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 x_c⁻. This is followed by an in-depth discussion of system x_c⁻ as it relates to glutamate release, cystine transport, and glutathione synthesis. Finally, the role of system x_c⁻ is surveyed across a number of psychiatric and neurodegenerative disorders.

Comments

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

Recommended Citation

Bridges, Richard; Lutgen, Victoria; Lobner, Doug; and Baker, David, "Thinking Outside the Cleft to Understand Synaptic Activity: Contribution of the Cystine-Glutamate Antiporter (System x_c⁻) to Normal and Pathological Glutamatergic Signaling" (2012). Biomedical Sciences Faculty Research and Publications. 12.
https://epublications.marquette.edu/biomedsci_fac/12