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Mechanistic and Structural Determinants of NMDA Receptor Voltage-Dependent Gating and Slow Mg2+ Unblock

NMDA receptor (NMDAR)-mediated currents depend on membrane depolarization to relieve powerful voltage-dependent NMDAR channel block by external magnesium (Mgo2+). Mgo2+ unblock from native NMDARs exhibits a fast component that is consistent with rapid Mgo2+-unbinding kinetics and also a slower, millisecond time scale component (slow Mgo2+ unblock). In recombinant NMDARs, slow Mgo2+ unblock is prominent in GluN1/2A (an NMDAR subtype composed of GluN1 and GluN2A subunits) and GluN1/2B receptors, with slower kinetics observed for GluN1/2B receptors, but absent from GluN1/2C and GluN1/2D receptors. Slow Mgo2+ unblock from GluN1/2B receptors results from inherent voltage-dependent gating, which increases channel open probability with depolarization. Here we examine the mechanisms responsible for NMDAR subtype dependence of slow Mgo2+ unblock. We demonstrate that slow Mgo2+ unblock from GluN1/2A receptors, like GluN1/2B receptors, results from inherent voltage-dependent gating. Surprisingly, GluN1/2A and GluN1/2B receptors exhibited equal inherent voltage dependence; faster Mgo2+ unblock from GluN1/2A receptors can be explained by voltage-independent differences in gating kinetics. To investigate the absence of slow Mgo2+ unblock in GluN1/2C and GluN1/2D receptors, we examined the GluN2 S/L site, a site responsible for several NMDAR subtype-dependent channel properties. Mutating the GluN2 S/L site of GluN2A subunits from serine (found in GluN2A and GluN2B subunits) to leucine (found in GluN2C and GluN2D) greatly diminished both voltage-dependent gating and slow Mgo2+ unblock. Therefore, the residue at the GluN2 S/L site governs the expression of both slow Mgo2+ unblock and inherent voltage dependence.