The AMPA subtype of ionotropic glutamate receptors (GluRs) mediate the vast majority of excitatory synaptic transmission in the mammalian CNS and participate in a variety of plastic changes in synaptic strength. One hallmark feature of these channels is that they desensitize in a few milliseconds, and at some CNS synapses desensitization contributes to shaping the decay of EPSCs. Because concentrations of glutamate in the low micromolar range can produce nearly complete desensitization, at most synapses desensitization likely occurs during single EPSCs and may even be significant at ambient levels of glutamate. Thus the rate at which channels recover from desensitization is a key determinant of the fidelity with which CNS neurons are able to follow high-frequency presynaptic firing. Here we propose a series of biophysical experiments designed to answer three questions about the kinetic and structural features that control recovery from AMPA-receptor desensitization. 1) What are the relative contributions of re-sensitization and ligand dissociation to the kinetics of recover and do they vary for different agonists? 2) To what extent is the ligand binding domain closed during desensitization and does this vary for individual subunits? 3) What are the structural determinants of the rate of recovery?
