N-Methyl-D-aspartate activates different channels than do kainate and quisqualate

In the mammalian central nervous system, the excitatory amino acid transmitter L-glutamate activates three pharmacologically distinguishable receptors, the N-methyl-D-aspartate (NMDA), kainate, and quisqualate receptors. The present paper addresses the issue of whether these three receptors operate independent channels or whether they share channels that may have several conductance substates. The Xenopus oocyte provides a system for expression of exogenous mRNAs that permits detailed study of receptor structure and function. In oocytes injected with rat brain mRNA, NMDA has a stoichiometry of channel activation different from that for kainate and quisqualate. NMDA activates its own channels as indicated by simple summation or near-summation of currents evoked by NMDA with those evoked by quisqualate or kainate. Deviations from summation are ascribable to lack of selectivity in which an agonist at one receptor acts as a weak antagonist at another receptor. A further indication of separate channels is that block of NMDA channels by Mg²⁺ or phencyclidine has no effect on kainate or quisqualate responses evoked during the block. Interactions of kainate and quisqualate are more complex, but they can be explained by lack of complete specificity of these agonists for their own receptors.