title: Inhibition of GTRAP3-18 may increase neuroprotective glutathione (GSH) synthesis.
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.
authors.affiliation: Department of Pharmacology, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi, Tokyo 173-8605, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Aoyama
authors.affiliation: Department of Pharmacology, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi, Tokyo 173-8605, Japan.
authors.forename: Toshio
authors.initials: T
authors.lastname: Nakaki
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D050580:Excitatory Amino Acid Transporter 3 / Q000378:metabolism; D005978:Glutathione / Q000096:biosynthesis*; D006360:Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D026901:Membrane Transport Proteins; D019636:Neurodegenerative Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D018696:Neuroprotective Agents / Q000627:therapeutic use*
chemical_list: C484566:ARL6IP5 protein, human; D050580:Excitatory Amino Acid Transporter 3; D006360:Heat-Shock Proteins; D047908:Intracellular Signaling Peptides and Proteins; D026901:Membrane Transport Proteins; D018696:Neuroprotective Agents; C493400:SLC1A1 protein, human; D005978:Glutathione
keywords: EAAC1; GTRAP3-18; cysteine uptake; glutathione; neurodegeneration