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NMDA Receptors Require Multiple Pre-opening Gating Steps for Efficient Synaptic Activity
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DOI：10.1016/j.neuron.2020.11.009.png)
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NMDA receptors (NMDARs) are glutamate-gated ion channels that mediate fast excitatory synaptic transmission in the nervous system. Applying glutamate to outside-out patches containing a single NMDAR, we find that agonist-bound receptors transition to the open state via two conformations, an unconstrained pre-active'' state that contributes to fast synaptic events and a constrained pre-active'' state that does not. To define how glutamate drives these conformations, we decoupled the ligand-binding domains from specific transmembrane segments for GluN1 and GluN2A. Displacements of the pore-forming M3 segments define the energy of fast opening. However, to enter the unconstrained conformation and contribute to fast signaling, the GluN2 pre-M1 helix must be displaced before the M3 segments move. This pre-M1 displacement is facilitated by the flexibility of the S2-M4 of GluN1 and GluN2A. Thus, outer structures-pre-M1 and S2-M4-work in concert to remove constraints and prime the channel for rapid opening, facilitating fast synaptic transmission.
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