Fig. 3.
System xc− (X)-mediated cystine uptake is a critical determinant of cellular antioxidant capabilities. In astrocytes, cystine (C-C) transported into the cell is reduced into Cys, which can then be used for GSH synthesis by the sequential activity of glutamate cysteine ligase (GCL) and GSH synthetase (GS). GSH can be released by astrocytes via muldrug resistance-asociated protein 1 (MRP-1) transporters, where it is degraded by γ-glutamyl-transpeptidase (γGT) and aminopeptidase N (AP-N). This provides an extracellular source of cysteine that is transported into neurons by the neuronal glutamate transporter EAAT3 (E) to support glutathione production in these cells. In addition, cysteine may also oxidize in the oxygen-rich extracellular space, thereby supplying cystine to support system xc− activity.