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 regulatory protein complexes, however a presynaptic equivalent to this signaling mechanism has not yet been identified. Novel evidence indicates that N-methyl-D-aspartate glutamate receptors may play a presynaptic role in synaptic plasticity. Thus, we investigated whether ionotropic glutamate receptor activation in isolated nerve terminals regulates neurotransmitter release, through nitric oxide formation. N-Methyl-D-aspartate dose-dependently inhibited the release of glutamate evoked by 4-aminopyridine (IC(50)=155 microM), and this effect was reversed by the N-methyl-D-aspartate receptor antagonist D-(-)-2-amino-5-phosphopentanoic acid and by the nitric oxide synthase inhibitor, L-nitroarginine, in synaptosomes isolated from whole hippocampus, CA3 and CA1 areas, but not from the dentate gyrus. In contrast, the 4-aminopyridine-evoked release of glutamate was reduced by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid or kainate by a nitric oxide-independent mechanism, 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 kainate, significantly increased cGMP formation. Presynaptic N-methyl-D-aspartate receptors are probably involved since removing extracellular nitric oxide with the scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl 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/nitric oxide inhibited the release of [3H]glutamate and [14C]GABA evoked by hypertonic sucrose. The results also suggest that presynaptic N-methyl-D-aspartate receptors may function as auto- and heteroreceptors.
Sequeira
S M
SM
Center for Neuroscience of Coimbra, Department of Zoology, Faculty of Science and Technology, University of Coimbra, 3004-517 Coimbra, Portugal.
Malva
J O
JO
Carvalho
A P
AP
Carvalho
C M
CM
D015761:4-Aminopyridine / Q000494:pharmacology; D000818:Animals; D002250:Carbon Radioisotopes; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D005089:Exocytosis / Q000187:drug effects / Q000502:physiology; D018698:Glutamic Acid / Q000493:pharmacokinetics; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism*; D007608:Kainic Acid / Q000494:pharmacology; D016202:N-Methylaspartate / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D017729:Presynaptic Terminals / Q000378:metabolism*; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D013574:Synaptosomes / Q000378:metabolism; D014316:Tritium; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000493:pharmacokinetics
D002250:Carbon Radioisotopes; D018690:Excitatory Amino Acid Agonists; D016194:Receptors, N-Methyl-D-Aspartate; D014316:Tritium; D009569:Nitric Oxide; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D016202:N-Methylaspartate; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D015761:4-Aminopyridine; D007608:Kainic Acid