Desensitization of NMDA receptor channels is modulated by glutamate agonists

Two distinct forms of desensitization have been characterized for N-methyl- D-aspartate (NMDA) receptors. One form results from a weakening of agonist affinity when channels are activated whereas the other form of desensitizat ion results when channels enter a long-lived nonconducting state. A weakeni ng of glycine affinity upon NMDA receptor activation has been reported. Cyc lic reaction schemes for NMDA receptor activation require that a concomitan t affinity shift should be observed for glutamate agonists. In this study, measurements of peak and steady-state NMDA receptor currents yielded EC50 v alues for glutamate that differed by 1.9-fold, but no differences were foun d for another agonist, L-cysteine-S-sulfate (LCSS). Simulations show that s hifts in EC50 values may be masked by significant degrees of desensitizatio n resulting from channels entering a long-lived nonconducting state. Simula tions also show that a decrease in the degree of desensitization with incre asing agonist concentration is a good indicator for the existence of desens itization resulting from a weakening of agonist affinity. Both glutamate an d LCSS exhibited this trend. An affinity difference of three- to eightfold between high-and low-affinity agonist-binding states was estimated from fit ting of dose-response data with models containing both types of desensitiza tion. This indicates that activation of NMDA receptors causes a reduction i n both glutamate and glycine affinities.