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Distribution of the Cystine/Glutamate Antiporter System x_c^– in the Brain, Kidney, and Duodenum

Joseph Burdo, Richard Dargusch and David Schubert

Cellular Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, California

Correspondence to: David Schubert, The Salk Institute for Biological Studies, 10010 N. Torrey Pines Rd., La Jolla, CA 92037. E-mail: Schubert{at}salk.edu

System x_c^–, one of the main transporters responsible for central nervous system cystine transport, is comprised of two subunits, xCT and 4F2hc. The transport of cystine into cells is rate limiting for glutathione synthesis, the major antioxidant and redox cofactor in the brain. Alterations in glutathione status are prevalent in numerous neurodegenerative diseases, emphasizing the importance of proper cystine homeostasis. However, the distribution of xCT and 4F2hc within the brain and other areas has not been described. Using specific antibodies, both xCT and 4F2hc were localized predominantly to neurons in the mouse and human brain, but some glial cells were labeled as well. Border areas between the brain proper and periphery including the vascular endothelial cells, ependymal cells, choroid plexus, and leptomeninges were also highly positive for the system x_c^– components. xCT and 4F2hc are also present at the brush border membranes in the kidney and duodenum. These results indicate that system x_c^– is likely to play a role in cellular health throughout many areas of the brain as well as other organs by maintaining intracellular cystine levels, thereby resulting in low levels of oxidative stress. (J Histochem Cytochem 54:549–557, 2006)

Key Words: xCT • system x_c^– • 4F2hc • glutathione • cystine • brain • duodenum • kidney • cystinuria

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