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Gating in the NMDA receptor is initiated in the extracellular ligand-binding domain (LBD) and is ultimately propagated via three linkers-S1-M1, M3-S2, and S2-M4-to the ion channel. M3-S2 directly couples LBD movements into channel gating, but the functional and structural contributions of S1-M1 and S2-M4 to the overall gating process are unknown. A scan of substituted cysteines in and around the NMDA receptor S1-M1 and S2-M4 with a bulky cysteine-reactive reagent identified numerous positions that showed potentiation of glutamate-activated as well as leak currents. As indexed by MK801 (dizocilpine hydrogen maleate), an open channel blocker, this potentiation was attributable to an increase in open probability, an interpretation confirmed for a subset of positions with single-channel recordings. The magnitude of this gating effect, acting through S1-M1 or S2-M4, was dependent on the intrinsic gating properties of the NMDA receptors, being more effective in the inherently low open probability GluN2C- than the higher open probability GluN2A-subunit-containing receptors. For the majority of these potentiation positions, we propose that alteration of gating arises from steric destabilization of contact interfaces where close apposition of the contacting partners is necessary for efficient channel closure. Our results therefore indicate that the NMDA receptor S1-M1 and S2-M4 linkers are dynamic during gating and can modulate the overall energetics of this process. Furthermore, the results conceptualize a mechanistic, as well as a possible structural, framework for pharmacologically targeting the linkers through noncompetitive and subunit-specific modes of action.

Specific Sites within the Ligand-Binding Domain and Ion Channel Linkers Modulate NMDA Receptor Gating