Toward a new role for plasma membrane sodium-dependent glutamate transporters of astrocytes: maintenance of antioxidant defenses beyond extracellular glutamate clearance

Abstract

The primary function assigned to the sodium-dependent glutamate transporters, also known as excitatory amino acid transporters (EAATs), is to maintain the extracellular glutamate concentration in the low micromolar range, allowing glutamate to be used as a signaling molecule in the brain and preventing its cytotoxic effects. However, glutamate and cyst(e)ine, that is also a substrate of EAATs, are also important metabolites used for instance in the synthesis of the main antioxidant glutathione. This review describes the evidence suggesting that EAATs, by providing glutathione precursors, are crucial to prevent oxidative death in particular cells of the nervous system while being dispensable in others. This differential importance may depend on the way antioxidant defenses are maintained in each cell type and on the metabolic fate of transported substrates, both being probably controlled by EAAT interacting proteins. As oxidative stress invariably contributes to various forms of cell death, a better understanding of how antioxidant defenses are maintained in particular brain cells will probably help to develop protective strategies in degenerative insults specifically affecting these cells.