INVOLVEMENT OF DIVALENT IONS IN THE NITRIC OXIDE-INDUCED BLOCKADE OF N-METHYL-D-ASPARTATE RECEPTORS IN CEREBELLAR GRANULE CELLS

We have previously shown that nitric oxide blocks the N-methyl-D-aspar tate (NMDA) receptor without affecting the agonist binding site. We no w report that in cerebellar granule cells nitric oxide decreases the N MDA channel conductance and open probability, in voltage-dependent and -independent manners, respectively, by acting on an extracellular sit e different from the redox, glycine, and pH modulatory sites of the re ceptor-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 N MDA receptors by NO donors.