Modal gating of GluN1/GluN2D NMDA receptors

• We evaluated GluN2D single channel recordings activated by glutamate and glycine.
• GluN1/GluN2D exhibits modal gating with brief periods of high open probability.
• The high open probability bursts have fewer shut duration components.
• The bursts were best fitted by a 3-closed and 2-open state gating model.
• The high mode opening and closing rate constants differed from the low mode rates.

GluN2D-containing NMDA receptors are characterized by an unusually low open probability (0.023), even in the presence of saturating glutamate and glycine. Here, we show that recombinant GluN1/GluN2D NMDA receptors can enter brief periods with exceptionally high open probability (0.65) in excised outside-out and cell-attached single channel recordings. GluN1/GluN2D channels during the enhanced gating mode have similar open durations as occurs outside of the high open probability burst of activity. However, the periods in the high gating mode only exhibit 4 brief closed duration exponential components similar to the briefest observed for openings outside the burst. GluN1/GluN2D receptors also open to a more prominent subconductance level compared to activity outside the high open probability burst. Evaluation of a five-state NMDA receptor gating model suggests that both the opening and closing rate constants differ for the periods of higher open probability compared to the high open probability arm of a gating model previously published for GluN1/GluN2D fit to a representative full length single channel recording. These data demonstrate that GluN2D-containing NMDA receptors can enter a conformation or mode that allows the pore to gate with high probability.