Regulation of Systemxc-by Pharmacological Manipulation of Cellular Thiols

Autor: Julie Hjelmhaug, Doug Lobner, David A. Baker, Rebecca Albano, Nicholas J Raddatz
Rok vydání: 2015
Předmět:
Zdroj: Oxidative Medicine and Cellular Longevity. 2015:1-9
ISSN: 1942-0994
1942-0900
DOI: 10.1155/2015/269371
Popis: The cystine/glutamate exchanger (systemxc-) mediates the transport of cystine into the cell in exchange for glutamate. By releasing glutamate, systemxc-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 systemxc-, 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 inhibitsγ-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 systemxc-in this culture system.
Databáze: OpenAIRE
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