Selective excitatory effects of γ-glutamyl-glycine, a glutathione metabolite, on GluN1 NMDA and mGlu5 receptors impacting synaptic plasticity.

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.