Effects of Ifenprodil on the Gating or NR1/2B NMDA Receptors
The extracellular amino terminal domain (ATD) of the NR2 subunits differentially controls NMDA receptor activity. Ifenprodil binds to the ATD of NR1/NR2B receptors inhibiting the receptors. To delineate the effects of ifenprodil on NR1/NR2B receptor gating, we recorded steady state currents from cell attached and excised outside out patches at pH7.9. NR1/NR2B receptors were found to exhibit modal gating in both forms of recording which was unaffected by ifenprodil. Ifenprodil increased the occupancy of the receptor in long-lived shut conformations hence reducing the open probability of receptor with no change in the mean open time. We found a negative correlation between the open and shut intervals in NR1/NR2B recordings from cell attached patches containing one active channel similar to those previously reported for NR1/NR2A receptors. In order to further understand actions of ifenprodil we fitted the single channel data to previously proposed models for NMDA receptor gating. Log likelihood criteria suggested that a cyclic model containing two uncoupled open states (Schorge et al. 2005) fitted the data better compared to a linear model with sequential open states. Ifenprodil modified multiple gating steps when fitted to an `uncoupled cyclic' model and promoted receptor desensitization. In contrast a single gating step was modified when single channel data was fitted to the `linear' gating model. Our results suggest an allosteric cross talk between the NR1 and NR2 subunits of the NMDA receptors.
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