NMDA channel behavior depends on agonist affinity

We have compared the kinetic properties of NMDA receptor channels activated by exogenous agonists with those activated synaptically. Short (4 msec) applications of L-glutamate to outside-out patches from hippocampal neurons evoked currents that decayed with a double exponential time course that was controlled by both the unbinding rate of agonist and receptor desensitization. Lower-affinity agonists evoked NMDA receptor-activated currents that had faster rates of decay and recovered from desensitization more quickly, consistent with the idea that agonists which dissociate faster allow the receptor to reach a desensitized state less often. Both synaptic and patch responses could be well fitted with a simple kinetic model comprised of two independent but identical binding sites, one open state, one closed state, and one desensitized state, all doubly liganded. Provided that the agonist has a slow unbinding rate relative to the rates into the open and desensitized states (e.g., L-glutamate), this model predicts a response with two decay phases and can thus account for the synaptic response. Since the unbinding rate is the critical determinant of the time course, different affinity transmitters would affect such properties as excitatory postsynaptic current (EPSC) duration. Of the known endogenous excitatory amino acids, only L-glutamate has an affinity for the NMDA receptor consistent with the time course of the EPSC recorded between hippocampal neurons in culture.