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L Fagni, M Olivier, M Lafon-Cazal and J Bockaert
Mecanismes Moleculaires des Communications Cellulaires, UPR CNRS 9023, Centre CNRS INSERM de Pharmacologie et d'Endocrinologie, Montpellier, France.
We have previously shown that nitric oxide blocks the N-methyl-D- aspartate (NMDA) receptor without affecting the agonist binding site. We now report that in cerebellar granule cells nitric oxide decreases the NMDA channel conductance and open probability, in voltage-dependent and -independent manners, respectively, by acting on an extracellular site different from the redox, glycine, and pH modulatory sites of the receptor-channel complex. This inhibition is not additive with those of Mg2+ and Zn2+. Moreover, removal of trace concentrations of metal ions in the external medium by means of metal ion-chelators significantly reduced the inhibitory action of nitric oxide on NMDA currents. These results indicate that divalent ions are required for the blockade of NMDA receptors by NO donors.
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