Glutathione is a physiologic reservoir of neuronal glutamate

Minori Koga, Anthony V. Serritella, Marcus M. Messmer, Akiko Hayashi-Takagi, Lynda D. Hester, Solomon H. Snyder, Akira Sawa, Thomas W. Sedlak*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

41 Scopus citations

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 1-10. mM. 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.

Original languageEnglish (US)
Pages (from-to)596-602
Number of pages7
JournalBiochemical and Biophysical Research Communications
Volume409
Issue number4
DOIs
StatePublished - Jun 17 2011
Externally publishedYes

Keywords

  • Antioxidants
  • Glutamate
  • Glutamyl cycle
  • Glutathione
  • Neurons
  • Neurotransmitter

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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