Figure 4. Schematic summary of NMDAR modulation by ligands and Ions.

Antagonism: The binding of competitive antagonists causes the ligand-binding domain (LBD) bi-lobe to close, resulting in the closing of the ion channel pore. Inhibition: Some allosteric inhibitors such as ifenprodil and Ro25-6981 bind at the GluN1–GluN2 amino-terminal domain (ATD) heterodimer interface and close the ATD bi-lobe, blocking the receptors in inactive conformations. Blocking: Channel blockers inhibit NMDAR by occluding the ion channel. Inhibition (Zn²⁺/H⁺-involvement): Zn²⁺ and protons induce clamshell closure in the GluN2 ATD and close the ion channel. Active/Open: Glycine/glutamate binding triggers conformational changes in the LBDs of GluN1/GluN2 NMDARs. The conformational rearrangement of the GluN1–GluN2 ATD couples the GluN1–GluN2 LBD with downstream gating.