Selective excitatory effects of γ‐glutamyl‐glycine, a glutathione metabolite, on GluN1 NMDA and mGlu5 receptors impacting synaptic plasticity
Abstract
Background and Purpose: Gamma‐glutamyl dipeptides are essentially produced after glutathione (GSH) degradation. While several γ‐glutamyl dipeptides have been detected in different organs and body fluids, their biological activity remains elusive. This is the case for γ‐Glutamyl‐Glycine (γ‐Glu‐Gly) which has been found in different brain areas. γ‐Glutamyl‐glycine may bind to ionotropic glutamate receptors. Here, we have investigated whether γ‐Glu‐Gly could exhibit modulatory actions on excitatory synaptic transmission and plasticity by performing its functional characterization on glutamate, GABA and glycine receptors. Experimental Approach: Electrophysiological and calcium imaging experiments were performed on cells heterologously expressing either Glutamate, GABA or Glycine receptors and on cultured hippocampal neurons and acute hippocampal slices. The γ‐Glu‐Gly production by cultured cells and hippocampal slices was measured by LC‐MS analysis, following incubation with modulators of the glutathione metabolic cycle. Key Results: γ‐Glu‐Gly exerted partial agonist effects on both NMDA GluN1 and mGlu5 receptors, but without any binding to the glutamate binding domain on both AMPA and NMDA GluN2A receptors. γ‐Glu‐Gly was devoid of any effect on GABA, glycine and GluN3A receptors. γ‐Glu‐Gly was able to trigger a long‐term increase in synaptic transmission in the CA1 area of mouse hippocampus. Conclusion and implications γ‐Glu‐Gly partially retains the excitatory actions of glutamate on specific receptor sub‐types and may trigger plastic events in the hippocampus. Its accumulation under pathological conditions associated with oxidative stress and a high GSH consumption could thus interfere with endogenous synaptic transmission and disrupt natural plasticity, which is a hallmark of neurodegenerative diseases.
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BibTeX
@article{andreu2026selective,
title = {{Selective excitatory effects of γ‐glutamyl‐glycine, a glutathione metabolite, on GluN1 NMDA and mGlu5 receptors impacting synaptic plasticity}},
author = {Sandro Andreu and Victoria Sonia Gizzi and Ugo Pasco and Fatiha Sebih and Yattou Zitouni and Pablo Jimenez and Valérie Rolland and Alain Chavanieu and Sébastien Estaran and Matthieu Rousset and Thierry Cens and Guillaume Cazals and Pierre Charnet and Janique Guiramand and Catherine Cohen‐solal and Claudine Ménard and Marie‐céleste de Jésus Ferreira and Nathalie Chevallier and Sonia Cantel and Michel Vignes and Julien Roussel},
journal = {British Journal of Pharmacology},
year = {2026},
month = sep,
doi = {10.1111/bph.70650},
url = {https://hal.science/hal-05738814v1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Selective excitatory effects of γ‐glutamyl‐glycine, a glutathione metabolite, on GluN1 NMDA and mGlu5 receptors impacting synaptic plasticity
AU - Sandro Andreu
AU - Victoria Sonia Gizzi
AU - Ugo Pasco
AU - Fatiha Sebih
AU - Yattou Zitouni
AU - Pablo Jimenez
AU - Valérie Rolland
AU - Alain Chavanieu
AU - Sébastien Estaran
AU - Matthieu Rousset
AU - Thierry Cens
AU - Guillaume Cazals
AU - Pierre Charnet
AU - Janique Guiramand
AU - Catherine Cohen‐solal
AU - Claudine Ménard
AU - Marie‐céleste de Jésus Ferreira
AU - Nathalie Chevallier
AU - Sonia Cantel
AU - Michel Vignes
AU - Julien Roussel
PY - 2026
DA - 2026/09/03
JO - British Journal of Pharmacology
DO - 10.1111/bph.70650
UR - https://hal.science/hal-05738814v1
AB - Background and Purpose: Gamma‐glutamyl dipeptides are essentially produced after glutathione (GSH) degradation. While several γ‐glutamyl dipeptides have been detected in different organs and body fluids, their biological activity remains elusive. This is the case for γ‐Glutamyl‐Glycine (γ‐Glu‐Gly) which has been found in different brain areas. γ‐Glutamyl‐glycine may bind to ionotropic glutamate receptors. Here, we have investigated whether γ‐Glu‐Gly could exhibit modulatory actions on excitatory synaptic transmission and plasticity by performing its functional characterization on glutamate, GABA and glycine receptors. Experimental Approach: Electrophysiological and calcium imaging experiments were performed on cells heterologously expressing either Glutamate, GABA or Glycine receptors and on cultured hippocampal neurons and acute hippocampal slices. The γ‐Glu‐Gly production by cultured cells and hippocampal slices was measured by LC‐MS analysis, following incubation with modulators of the glutathione metabolic cycle. Key Results: γ‐Glu‐Gly exerted partial agonist effects on both NMDA GluN1 and mGlu5 receptors, but without any binding to the glutamate binding domain on both AMPA and NMDA GluN2A receptors. γ‐Glu‐Gly was devoid of any effect on GABA, glycine and GluN3A receptors. γ‐Glu‐Gly was able to trigger a long‐term increase in synaptic transmission in the CA1 area of mouse hippocampus. Conclusion and implications γ‐Glu‐Gly partially retains the excitatory actions of glutamate on specific receptor sub‐types and may trigger plastic events in the hippocampus. Its accumulation under pathological conditions associated with oxidative stress and a high GSH consumption could thus interfere with endogenous synaptic transmission and disrupt natural plasticity, which is a hallmark of neurodegenerative diseases.
SN - 0007-1188
SN - 1476-5381
ER -