Regulation of System x_c^- by Pharmacological Manipulation of Cellular Thiols

Authors

Rebecca Albano, Marquette UniversityFollow
Nicholas J. Raddatz, Marquette UniversityFollow
Julie Hjelmhaug, Marquette UniversityFollow
David Baker, Marquette UniversityFollow
Doug Lobner, Marquette UniversityFollow

Document Type

Article

Language

eng

Format of Original

9 p.

Publication Date

2015

Publisher

Hindawi Publishing Corporation

Source Publication

Oxidative Medicine and Cellular Longevity

Source ISSN

1942-0994

Original Item ID

DOI: 10.1155/2015/269371; PMCID: PMC4407525

Abstract

The cystine/glutamate exchanger (system x_c^-) mediates the transport of cystine into the cell in exchange for glutamate. By releasing glutamate, system x_c^- can potentially cause excitotoxicity. However, through providing cystine to the cell, it regulates the levels of cellular glutathione (GSH), the main endogenous intracellular antioxidant, and may protect cells against oxidative stress. We tested two different compounds that deplete primary cortical cultures containing both neurons and astrocytes of intracellular GSH, L-buthionine-sulfoximine (L-BSO), and diethyl maleate (DEM). Both compounds caused significant concentration and time dependent decreases in intracellular GSH levels. However; DEM caused an increase in radiolabeled cystine uptake through system x_c^- , while unexpectedly BSO caused a decrease in uptake. The compounds caused similar low levels of neurotoxicity, while only BSO caused an increase in oxidative stress. The mechanism of GSH depletion by these two compounds is different, DEM directly conjugates to GSH, while BSO inhibits γ-glutamylcysteine synthetase, a key enzyme in GSH synthesis. As would be expected from these mechanisms of action, DEM caused a decrease in intracellular cysteine, while BSO increased cysteine levels. The results suggest that negative feedback by intracellular cysteine is an important regulator of system x_c^- in this culture system.

Comments

Published version. Oxidative Medicine and Cellular Longevity, Vol. 2015, No. 269371 (2015): 1-9. DOI. © 2015 Rebecca Albano et al. Used with permission.

Creative Commons License

This work is licensed under a Creative Commons Attribution 3.0 License.

Recommended Citation

Albano, Rebecca; Raddatz, Nicholas J.; Hjelmhaug, Julie; Baker, David; and Lobner, Doug, "Regulation of System x_c^- by Pharmacological Manipulation of Cellular Thiols" (2015). Biomedical Sciences Faculty Research and Publications. 167.
https://epublications.marquette.edu/biomedsci_fac/167