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.