N‐methyl‐D‐aspartate autoreceptors respond to low and high agonist concentrations by facilitating, respectively, exocytosis and carrier‐mediated release of glutamate in rat hippocampus

Abstract

Presynaptic NMDA autoreceptors regulating glutamate release have rarely been investigated. High-micromolar N-methyl-D-aspartate (NMDA) was reported to elicit glutamate release from hippocampal synaptosomes in a Ca(2+)-independent manner by reversal of excitatory amino acid transporters. The aim of this work was to characterize excitatory amino acid release evoked by low-micromolar NMDA from glutamatergic axon terminals. Purified rat hippocampal synaptosomes were prelabelled with [(3)H]D-aspartate ([(3)H]D-ASP) and exposed in superfusion to varying concentrations of NMDA in the presence of 1 microM glycine. The release of [(3)H]D-ASP and also that of endogenous glutamate provoked by 10 microM NMDA were external Ca(2+) dependent and sensitive to the NMDA channel blocker MK-801 but insensitive to the glutamate transporter inhibitor DL-TBOA, which, on the contrary, prevented the Ca(2+)-independent release evoked by 100 microM NMDA. The NMDA (10 microM) response was blocked by 1 nM Zn(2+) and 1 microM ifenprodil, compatible with the involvement of a NR1/NR2A/NR2B assembly, although the presence of two separate receptor populations, i.e., NR1/NR2A and NR1/NR2B, cannot be excluded. This response was strongly antagonized by submicromolar (0.01-1 microM) concentrations of kynurenic acid and was mimicked by quinolinic acid (1-100 microM) plus 1 microM glycine. Finally, the HIV-1 protein gp120 potently mimicked the NMDA co-agonists glycine and D-serine, being significantly effective at 30 pM. In conclusion, glutamatergic nerve terminals possess NMDA autoreceptors mediating different types of release when activated by different agonist concentrations: low-micromolar glutamate would potentiate glutamate exocytosis, whereas higher glutamate concentrations would also provoke carrier-mediated release.

Salicylate Enables Cochlear Arachidonic-Acid-Sensitive NMDA Receptor Responses

“…Consequently, the increase of the spontaneous spiking rate observed during perilymphatic perfusion of salicylate in vivo may partially be attributable to an activation of NMDA autoreceptors on the IHCs, which in turn would increase Glu release, as described previously in the CNS (Berretta and Jones, 1996;Breukel et al, 1998;Woodhall et al, 2001;Yang et al, 2006;Luccini et al, 2007). However, the excitatory effect of NaSal in the presence of GYKI 53784, which completely inhibits AMPA receptors (Ruel et al, 2000), argues against an activation of IHC NMDA autoreceptors as a unique mechanism of NaSal action.…”

Presynaptic c-Jun N-terminal Kinase 2 regulates NMDA receptor-dependent glutamate release

“…The radiactive tracer allows to measure glutamate exocytosis from isolated nerve terminals avoiding the problems related to the enzymatic degradation of glutamate2425. From here on, throughout the manuscript, the release of preloaded [3H]D-ASP will be referred to as glutamate release.…”

Novel Aspect of Ketone Action: β-Hydroxybutyrate Increases Brain Synthesis of Kynurenic Acid In Vitro

“…It is lower though, than after in vivo application of KYNA precursor, L-kynurenine together with probenecid, reported to increase brain KYNA several-fold (Miranda et al 1997;Shepard et al 2003). Yet, having in mind that already nanomolar levels of KYNA block a7 nicotinic receptors and reduce the presynaptic release of glutamate (Carpenedo et al 2001;Hilmas et al 2001;Luccini et al 2007), found enhancement of KYNA synthesis evoked by BHB seems to be clinically relevant, especially as regards potential neuroprotective effects of ketone bodies.…”

“…However, recent discoveries have reinforced the hypothesis suggesting an important role of KYNA in brain physiology and pathology. It was demonstrated that high nanomolar levels of KYNA are sufficient to block noncompetitively a7 nicotinic receptors or to increase the expression of a4b2 nicotinic receptors, whereas low nanomolar amounts of compound reduce the presynaptic release of glutamate (Carpenedo et al 2001;Hilmas et al 2001;Luccini et al 2007).…”