Frontiers in Pharmacology (Jan 2022)

The Glutathione Metabolite γ-Glutamyl-Glutamate Partially Activates Glutamate NMDA Receptors in Central Neurons With Higher Efficacy for GluN2B-Containing Receptors

  • Fatiha Sebih,
  • Nawfel Mokrane,
  • Pierre Fontanel,
  • Mete Kayatekin,
  • Mahira Kaabeche,
  • Janique Guiramand,
  • Catherine Cohen-Solal,
  • Thierry Cens,
  • Matthieu Rousset,
  • Pierre Charnet,
  • Marie-Céleste De Jésus Ferreira,
  • Jean-Baptiste Thibaud,
  • Claudine Ménard,
  • Sonia Cantel,
  • Valérie Rolland,
  • Michel Vignes,
  • Julien Roussel

DOI
https://doi.org/10.3389/fphar.2021.794680
Journal volume & issue
Vol. 12

Abstract

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Gamma-L-glutamyl-L-glutamate (γ-Glu-Glu) was synthetized and further characterized for its activity on cultured neurons. We observed that γ-Glu-Glu elicited excitatory effects on neurons likely by activating mainly the N-methyl-D-aspartate (NMDA) receptors. These effects were dependent on the integrity of synaptic transmission as they were blocked by tetrodotoxin (TTX). We next evaluated its activity on NMDA receptors by testing it on cells expressing these receptors. We observed that γ-Glu-Glu partially activated NMDA receptors and exhibited better efficacy for NMDA receptors containing the GluN2B subunit. Moreover, at low concentration, γ-Glu-Glu potentiated the responses of glutamate on NMDA receptors. Finally, the endogenous production of γ-Glu-Glu was measured by LC-MS on the extracellular medium of C6 rat astroglioma cells. We found that extracellular γ-Glu-Glu concentration was, to some extent, directly linked to GSH metabolism as γ-Glu-Glu can be a by-product of glutathione (GSH) breakdown after γ-glutamyl transferase action. Therefore, γ-Glu-Glu could exert excitatory effects by activating neuronal NMDA receptors when GSH production is enhanced.

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