Modal gating of NMDA receptors and the shape of their synaptic response

N-methyl-D-aspartate receptor (NMDAR) channels mediate the slow component of excitatory potentials at glutamatergic synapses. They have complex kinetic behavior, and much remains to be understood about NMDAR gating mechanisms and the molecular events that shape the synaptic current. Here we show that an individual NMDAR produces at least three stable patterns of activity. For all modes, channels gate by the same mechanism and can occupy either of two open states. The relative stability of the open states differs across modes because of a common perturbation to the NMDAR structure that may be subject to cellular control. Simulations indicate that native NMDAR-mediated synaptic responses arise mainly from the most common mode, and that the slow rise and decay of the current can be attributed to multiple transitions between fully liganded open and closed states rather than to agonist dissociation.