Non-classical glutamate receptors, blocked by both NMDA and non-NMDA antagonists, stimulate nitric oxide production in neurons.

In striatal neurons in primary culture, kainate and domoate stimulated cGMP production, whereas two other analogs of glutamate which act at non-NMDA receptors, alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionate (AMPA) and quisqualate were ineffective. However, both agonists stimulated cGMP accumulation on neurons pretreated with concanavalin A, a lectin which is known to prevent desensitization of AMPA receptors. We show here that such a treatment also potentiated the kainate-stimulated cGMP production. Responses induced by all agonists of non-NMDA receptors tested were mediated by nitric oxide (NO) production, since they were inhibited by haemoglobin, an NO scavenger, and two competitive inhibitors of NO-synthase L-NG-monomethylarginine and L-NG-nitro-arginine, the effects of both inhibitors being reversed by an excess of L-arginine. The rank order of potency of the agonists tested (domoate > kainate approximately AMPA approximately quisqualate) suggests that a kainate receptor subtype triggers NO production in striatal neurons. Surprisingly, response evoked by maximally effective concentrations of kainate, quisqualate and AMPA on concanavalin A-treated neurons were partially antagonized by two non-competitive antagonists of NMDA receptors, MK-801 and phencyclidine, and by Mg2+ ions, which block NMDA-operated channels. However, in neurons which had not been treated with concanavalin A, kainate-induced NO production was not inhibited by these antagonists. These results suggest that, in addition to kainate receptor subtype, another glutamate receptor subtype which may be composed of both kainate and NMDA receptor subunits and which is desensitized by kainate, AMPA and quisqualate, is involved in NO production.