Glutamate partner drives gamma-glutamyl-dipeptide effects on ionotropic glutamate receptors

Description

Gamma-glutamyl dipeptides are yielded by the condensation of glutamate with another amino acid on the gamma position. Their synthesis results from the hydrolysis of glutathione (GSH ; gamma-Glu-Cys-Gly) by gamma- glutamyl transferase (GGT). In fact, while g-glutamyl dipeptides have been detected in different organs and fluids of the body, especially in the brain, their biological activity remains elusive. Nevertheless, binding studied have revealed that they could bind glutamate ionotropic receptors, i.e. AMPA, kainate and NMDA subtypes. In the present work, we have examined the activity of two of them, gamma-Glu-Gly and gamma- Glu-Lys, which exhibit high affinity for ionotropic glutamate receptors. They were synthetized as previously described (Sebih et al., Frontiers in Pharmacology, 2022) and LC-MS analyses indicated that both dipeptides production by atrocytic C6 cell line is tightly linked to the integrity of GSH metabolism. They were further tested on both AMPA and NMDA receptors-expressing cells and acute hippocampal slices. gamma- Glu-Gly displayed both co-agonist activity on NMDA receptor Glycine site and partial agonism on AMPA receptors. Interestingly, gamma-Glu-Gly potentiated excitatory synaptic transmission. gamma-Glu-Lys elicited antogonist action on AMPA receptors which resulted in short- and long-lasting synaptic depression. However, gamma-Glu-Lys had no effect on NMDA receptors. Therefore, the amino acid associated to glutamate in gamma- glutamyl dipeptides governs their selectivity towards ionotropic glutamate receptors. The accumulation of g-glutamyl dipeptides within the brain under pathological conditions associated to oxidative stress and high GSH consumption could thus contribute to excitatory synaptic transmission and plasticity disruption which is a hallmark of neurodegenerative diseases.

Abstract

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