Arcaine and magnesium inhibition of the NMDA receptor ionophore complex: Evidence for distinct voltage-dependent sites

The inhibitory effects of the polyamine antagonist, arcaine, and magnesium on N-methyl-D-aspartate (NMDA) induced hippocampal [³H]norepinephrine release and [piperidyl-3,4-³H(N)]-[N-1-(2-thienyl)cyclohexyl]-3,4-piperidine (TCP) binding were studied. We report that the inhibitory effect of arcaine and magnesium on NMDA-induced [³H]norepinephrine release is diminished by increasing the extracellular K⁺ concentration, presumably reflecting a voltage-dependent block for both. However, unlike MK-801, the block by arcaine shows no evidence of use dependence. Further, the IC₅₀ value for magnesium inhibition of [piperidyl-3,4-³H(N)]TCP binding varies with the state of activation of the channel, being the lowest when the channel is maximally activated and the highest when the channel is least activated. On the other hand, the apparent affinity of arcaine is not significantly affected by the activation of the channel by glutamate and glycine, but is decreased by the polyamine agonist, spermidine. These data suggest that the polyamine antagonist binding site is distinct from either the phencyclidine/MK-801 site or the voltage-dependent channel site for magnesium. Nonetheless, these data suggest that the site must be located in a region of the NMDA receptor ionophore complex capable of sensing transmembrane potential.