Presynaptic N-methyl-D-aspartate receptor activation inhibits neurotransmitter release through nitric oxide formation in rat hippocampal nerve terminals

In brain synapses, nitric oxide synthase activation is coupled to N-methyl- D-aspartate-mediated calcium entry at postsynaptic densities through regula tory protein complexes, however a presynaptic equivalent to this signaling mechanism has not yet been identified. Novel evidence indicates that N-meth yl-D-aspartate glutamate receptors may play a presynaptic role in synaptic plasticity. Thus, we investigated whether ionotropic glutamate receptor act ivation in isolated nerve terminals regulates neurotransmitter release, thr ough nitric oxide formation. N-Methyl-D-aspartate dose-dependently inhibite d the release of glutamate evoked by 4-aminopyridine (IC50=155 muM). and th is effect was reversed by the N-methyl-D-aspartate receptor antagonist D-(- )-2-amino-5-phosphopentanoic acid and by the nitric oxide synthase inhibito r, L-nitroarginine, in synaptosomes isolated from whole hippocampus, CA3 an d CA1 areas, but not from the dentate gyrus. In contrast, the 4-aminopyridi ne-evoked release of glutamate was reduced by alpha -amino-3-hydroxy-5-meth yl-4-isoxazolepropionic acid or kainate by a nitric oxide-independent mecha nism, since it was not blocked by L-nitroarginine, and N-methyl-D-aspartate , but not alpha -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid or kain ate, significantly increased cGMP formation. Presynaptic N-methy-D-aspartat e receptors are probably involved since removing extracellular nitric oxide with the scavenger 2-(4-carboxyphenyl)-4,4,5,5 tetramethylimidazoline-1-ox yl 3-oxide did not block the depression of glutamate release by N-methyl-D- aspartate. The mechanism underlying this depression involves the inhibition of synaptic vesicle exocytosis since N-methyl-D-aspartate I nitric oxide i nhibited the release of [H-3]glutamate and [C-14]GABA evoked by hypertonic sucrose. The results also suggest that presynaptic N-methyl-D-aspartate rec eptors may function as auto- and heteroreceptors. (C) 2001 Elsevier Science BN. All rights reserved.