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Inhibition of GTRAP3-18 May Increase Neuroprotective Glutathione (GSH) Synthesis
Department of Pharmacology, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi, Tokyo 173-8605, Japan
* Author to whom correspondence should be addressed.
Received: 9 July 2012; in revised form: 6 August 2012 / Accepted: 10 September 2012 / Published: 20 September 2012
Abstract: Glutathione (GSH) is a tripeptide consisting of glutamate, cysteine, and glycine; it has a variety of functions in the central nervous system. Brain GSH depletion is considered a preclinical sign in age-related neurodegenerative diseases, and it promotes the subsequent processes toward neurotoxicity. A neuroprotective mechanism accomplished by increasing GSH synthesis could be a promising approach in the treatment of neurodegenerative diseases. In neurons, cysteine is the rate-limiting substrate for GSH synthesis. Excitatory amino acid carrier 1 (EAAC1) is a neuronal cysteine/glutamate transporter in the brain. EAAC1 translocation to the plasma membrane promotes cysteine uptake, leading to GSH synthesis, while being negatively regulated by glutamate transport associated protein 3-18 (GTRAP3-18). Our recent studies have suggested GTRAP3-18 as an inhibitory factor for neuronal GSH synthesis. Inhibiting GTRAP3-18 function is an endogenous mechanism to increase neuron-specific GSH synthesis in the brain. This review gives an overview of EAAC1-mediated GSH synthesis, and its regulatory mechanisms by GTRAP3-18 in the brain, and a potential approach against neurodegeneration.
Keywords: glutathione; cysteine uptake; GTRAP3-18; EAAC1; neurodegeneration
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Aoyama, K.; Nakaki, T. Inhibition of GTRAP3-18 May Increase Neuroprotective Glutathione (GSH) Synthesis. Int. J. Mol. Sci. 2012, 13, 12017-12035.
Aoyama K, Nakaki T. Inhibition of GTRAP3-18 May Increase Neuroprotective Glutathione (GSH) Synthesis. International Journal of Molecular Sciences. 2012; 13(9):12017-12035.
Aoyama, Koji; Nakaki, Toshio. 2012. "Inhibition of GTRAP3-18 May Increase Neuroprotective Glutathione (GSH) Synthesis." Int. J. Mol. Sci. 13, no. 9: 12017-12035.