title: A dominant role of GTRAP3-18 in neuronal glutathione synthesis.
abstract: 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.
authors.affiliation: Department of Pharmacology, Teikyo University School of Medicine, Tokyo 173-8605, Japan.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Watabe
authors.forename: Koji
authors.initials: K
authors.lastname: Aoyama
authors.forename: Toshio
authors.initials: T
authors.lastname: Nakaki
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D003545:Cysteine / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics; D050580:Excitatory Amino Acid Transporter 3 / Q000378:metabolism*; D005978:Glutathione / Q000096:biosynthesis*; D006360:Heat-Shock Proteins; D007150:Immunohistochemistry; D008297:Male; D026901:Membrane Transport Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000378:metabolism*; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology; D018384:Oxidative Stress / Q000235:genetics*; D034622:RNA Interference; D051381:Rats
chemical_list: C464502:Arl6ip5 protein, mouse; D002352:Carrier Proteins; D050580:Excitatory Amino Acid Transporter 3; D006360:Heat-Shock Proteins; D026901:Membrane Transport Proteins; D020319:Oligodeoxyribonucleotides, Antisense; C493398:Slc1a1 protein, rat; D005978:Glutathione; D003545:Cysteine
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