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Modulation of neuronal glutathione synthesis by EAAC1 and its interacting protein GTRAP3-18

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Abstract

Glutathione (GSH) plays essential roles in different processes such as antioxidant defenses, cell signaling, cell proliferation, and apoptosis in the central nervous system. GSH is a tripeptide composed of glutamate, cysteine, and glycine. The concentration of cysteine in neurons is much lower than that of glutamate or glycine, so that cysteine is the rate-limiting substrate for neuronal GSH synthesis. Most neuronal cysteine uptake is mediated through the neuronal sodium-dependent glutamate transporter, known as excitatory amino acid carrier 1 (EAAC1). Glutamate transporters are vulnerable to oxidative stress and EAAC1 dysfunction impairs neuronal GSH synthesis by reducing cysteine uptake. This may start a vicious circle leading to neurodegeneration. Intracellular signaling molecules functionally regulate EAAC1. Glutamate transporter-associated protein 3-18 (GTRAP3-18) activation down-regulates EAAC1 function. Here, we focused on the interaction between EAAC1 and GTRAP3-18 at the plasma membrane to investigate their effects on neuronal GSH synthesis. Increased level of GTRAP3-18 protein induced a decrease in GSH level and, thereby, increased the vulnerability to oxidative stress, while decreased level of GTRAP3-18 protein induced an increase in GSH level in vitro. We also confirmed these results in vivo. Our studies demonstrate that GTRAP3-18 regulates neuronal GSH level by controlling the EAAC1-mediated uptake of cysteine.

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  1. Department of Pharmacology, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi, Tokyo, 173-8605, Japan

    Koji Aoyama, Masahiko Watabe & Toshio Nakaki

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  1. Koji Aoyama
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  2. Masahiko Watabe
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Aoyama, K., Watabe, M. & Nakaki, T. Modulation of neuronal glutathione synthesis by EAAC1 and its interacting protein GTRAP3-18. Amino Acids 42, 163–169 (2012). https://doi.org/10.1007/s00726-011-0861-y

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