title: Glutathione is a physiologic reservoir of neuronal glutamate.
abstract: Glutamate, the principal excitatory neurotransmitter of the brain, participates in a multitude of physiologic and pathologic processes, including learning and memory. Glutathione, a tripeptide composed of the amino acids glutamate, cysteine, and glycine, serves important cofactor roles in antioxidant defense and drug detoxification, but glutathione deficits occur in multiple neuropsychiatric disorders. Glutathione synthesis and metabolism are governed by a cycle of enzymes, the γ-glutamyl cycle, which can achieve intracellular glutathione concentrations of 1-10mM. Because of the considerable quantity of brain glutathione and its rapid turnover, we hypothesized that glutathione may serve as a reservoir of neural glutamate. We quantified glutamate in HT22 hippocampal neurons, PC12 cells and primary cortical neurons after treatment with molecular inhibitors targeting three different enzymes of the glutathione metabolic cycle. Inhibiting 5-oxoprolinase and γ-glutamyl transferase, enzymes that liberate glutamate from glutathione, leads to decreases in glutamate. In contrast, inhibition of γ-glutamyl cysteine ligase, which uses glutamate to synthesize glutathione, results in substantial glutamate accumulation. Increased glutamate levels following inhibition of glutathione synthesis temporally precede later effects upon oxidative stress.
authors.affiliation: Department of Psychiatry and Behavioral Sciences, The Johns Hopkins University School of Medicine, Meyer 4-137, 600 North Wolfe Street, Baltimore, MD 21287, USA. mkoga3@jhmi.edu
authors.forename: Minori
authors.initials: M
authors.lastname: Koga
authors.forename: Anthony V
authors.initials: AV
authors.lastname: Serritella
authors.forename: Marcus M
authors.initials: MM
authors.lastname: Messmer
authors.forename: Akiko
authors.initials: A
authors.lastname: Hayashi-Takagi
authors.forename: Lynda D
authors.initials: LD
authors.lastname: Hester
authors.forename: Solomon H
authors.initials: SH
authors.lastname: Snyder
authors.forename: Akira
authors.initials: A
authors.lastname: Sawa
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Sedlak
mesh_terms: D000818:Animals; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018698:Glutamic Acid / Q000096:biosynthesis*; D005978:Glutathione / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology; D048288:Imidazolines / Q000494:pharmacology; D007555:Isoxazoles / Q000494:pharmacology; D051379:Mice; D009474:Neurons / Q000378:metabolism*; D011752:Pyroglutamate Hydrolase / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D005723:gamma-Glutamyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: C560753:2-imidazolidone-4-carboxylic acid; D004791:Enzyme Inhibitors; D048288:Imidazolines; D007555:Isoxazoles; D018698:Glutamic Acid; D019328:Buthionine Sulfoximine; D005723:gamma-Glutamyltransferase; D011752:Pyroglutamate Hydrolase; D005978:Glutathione; C006303:acivicin