Displacement of excitatory amino acid receptor ligands by acidic oligopeptides

Abstract

A number of L-glutamyl and L-aspartyl dipeptides, glutathione, gamma-D-glutamylglycine and gamma-D-glutamyltaurine, were tested for their efficacy to displace ligands specific for different subtypes of excitatory amino acid receptors from rat brain synaptic membranes. In general, the L enanthiomorphs of gamma-glutamyl peptides were more potent displacers than gamma-D-glutamylglycine and -taurine but the latter were more specific for the quisqualate type of receptors. gamma-L-glutamyl-L-glutamate was the most effective dipeptide in displacing the binding of glutamate, 2-amino-3-hydroxy-5-methylisoxazole-4-proprionate (AMPA) and 2-amino-5-phosphonoheptanoate (APH), whereas gamma-L-glutamyl-L-aspartate was the most effective in the binding of kainate. Both oxidized and reduced glutathione were inhibitory, being most potent in the binding of AMPA. gamma-L-Glutamylaminomethylsulphonate was most effective in the binding of APH. The most potent gamma-L-glutamyl peptides (glutathione, gamma-L-glutamyl-L-glutamate, -L-aspartate, and -glycine) may act as endogenous modulators of excitatory aminoacidergic neurotransmission.

Thinking Outside the Cleft to Understand Synaptic Activity: Contribution of the Cystine-Glutamate Antiporter (System xc−) to Normal and Pathological Glutamatergic Signaling

“…It has also been reported to evoke excitatory potentials in rat cortical slices and to regulate the release of other 788 transmitters, although it remains to be determined whether these actions are mediated via a specific "glutathione receptor" or through other systems, such as excitatory amino acid receptors (Shaw et al, 1996;Janáky et al, 1999;Oja et al, 2000 (Ogita et al, 1995;Janá ky et al, 1999), suggesting that glutathione actions may vary between agonist and antagonist on the basis of specific conditions. Glutathione was also shown to block the binding of radiolabeled AMPA and kainate to non-NMDA receptors (Varga et al, 1989). In a study employing computational modeling, the amino acid binding pockets common to family C G-protein-coupled receptors were probed in silico for the potential to accommodate glutathione .…”

Modulation of Sensory and Excitatory Amino Acid Responses by Nitric Oxide Donors and Glutathione in the Ventrobasal Thalamus of the Rat

“…Glutathione has been reported to have a number of varied actions upon excitatory amino acid neurotransmission. Immunostaining has revealed the presence of binding sites located on astrocytes Guo etal., 1992) while other work has revealed the capacity of glutathione to displace glutamate from its binding sites (Ogita etal., 1986;Ogita and Yoneda, 1988) and possibly to exert an effect on excitatory amino acid neurotransmission directly (Varga et al, 1989;Ogita et al, 1995) and via its effect on the redox state of the NMDA receptor (Janiky etal., 1993). The data from the present study suggest that glutathione in both its reduced and oxidized forms has an inhibitory effect on excitatory amino acid neurotransmission in VB; GSH inhibited responses to NMDA, AMPA and physiological stimuli, while GSSG inhibited only responses to NMDA.…”

Modulation of [3H]Dopamine Release by Glutathione in Mouse Striatal Slices

“…(4) Indirectly as a competitive c-glutamyl antagonist at the NMDA receptors on inhibitory GABAergic interneurons. Our earlier studies [8,42] and those of others [43,44] have shown that glutathione acts at both NMDA and non-NMDA receptors. Agonists of these receptors enhance dopamine release in striatal slices which effects are blocked by their respective antagonists [45,46].…”

“…GSH release from brain slices upon depolarization has also been shown to occur [5]. On the other hand, glutathione also acts as a neuromodulator at glutamate receptors [6][7][8][9][10][11]. We have found that both GSH and GSSG preferably interact with 2-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) and N-methyl-D-aspartate (NMDA) receptors.…”

“…We have found that both GSH and GSSG preferably interact with 2-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) and N-methyl-D-aspartate (NMDA) receptors. Since both of these receptors contain functional thiol groups [12,13] and the NMDA receptor also a glycine co-activatory site, several modes of interaction are possible [6][7][8][9][10][11]. Moreover, hippocampal [ 3 H]GABA release is altered by both GSH and GSSG [9].The released GSH may also affect the release of other neurotransmitters via its own receptors [3,4,14].…”