Aspartate as a selective NMDA receptor agonist in cultured cells from the avian retina

Although glutamate is considered the natural neurotransmitter that mediates excitatory function in the CNS, other active natural compounds can also drive the functional activation of excitatory amino acid receptors (EAAR). L-aspartate is the most likely neurotransmitter to mimic the actions of glutamate. Here we show that L-aspartate promotes the release of GABA acting selectively on the NMDA receptor subtype. Retina cell cultures, when exposed to excitatory amino acids (EAA), release [3H] GABA previously incorporated by the cells. Both L-glutamate and L- and D-aspartate at 100 microM concentration, promote the release which can be mimicked by kainate and NMDA. While aspartate-induced release of [3H] GABA occurs in the presence of 1 mM Mg2+, NMDA (100 microM) promotes the release only when Mg2+ is omitted from the superfusing medium. However, in the absence of Mg2+ the efficacy of 1- and d-aspartate (100 microM) to activate [3H] GABA release increases by a factor of 2 when compared to the release observed in the presence of 1 mM Mg2+. NMDA and aspartate induced release of [3H] GABA is completely inhibited by 10 microM MK-801 and is not affected by CNQX (100 microM). In the presence of Mg2+, aspartate-induced release of [3H] GABA is also completely inhibited by MK-801 (10 microM) and is not significantly affected by CNQX (100 microM). The [3H] GABA release induced by kainate (100 microM) is fully inhibited by CNQX (100 microM) and is not affected by MK-801 (10 microM). Our results indicate that in the retina, l-aspartate modulates its excitatory function on a set of GABAergic cells via the selective activation of NMDA receptors. The fact that L- and D-aspartate (but not D-glutamate) induce the release of GABA even in the presence of Mg2+ suggests that the electrogenic uptake of aspartate is required to lower the affinity of the NMDA channel for Mg2+. The observation that D-glutamate (200 microM), which is not taken up by the cells, activates the efflux of GABA only when Mg2+ is omitted from the incubating medium, supports this possibility.