A dominant role of GTRAP3-18 in neuronal glutathione synthesis

Glutathione is an essential reductant which protects cells and is reduced in neurodegenerative disorders such as Parkinson's and Alzheimer's diseases. Neurons rely mainly on extracellular cysteine for glutathione synthesis and a cysteine transporter termed excitatory amino acid carrier 1 (EAAC1). However, the mechanisms underlying neuronal cysteine uptake have remained elusive. Herein, we show glutamate transport-associated protein for EAAC1 (GTRAP3-18) to interact with EAAC1 at the plasma membrane and thereby regulate neuronal glutathione levels. Glutathione increased in the mouse brain as well as in primary cultured neurons, when the GTRAP3-18 protein level was decreased by genetic manipulations, whereas glutathione decreased when GTRAP3-18 was increased. Furthermore, glutathione contents that had been increased, by a translocator and activator of EAAC1, were suppressed by increased cell surface GTRAP3-18 protein. Our results demonstrate GTRAP3-18 to dominantly and negatively determine the intracellular glutathione contents in neurons.