Fig. 1: Architecture of the NMDA receptors and their ion channel.

a NMDARs function as tetramers (2 GluN1/2 GluN2 subunits) with four domains in each subunit: extracellular amino-terminal (ATD) and ligand-binding (LBD) domains; transmembrane domain (TMD) forming the ion channel; and an intracellular C-terminal domain (not shown). GluN1/GluN2B, 6WHR²⁵. b In homology to an inverted K⁺ channels, the ion channel core is the pore domain: transmembrane helices M1 ( = TM1 or S5) (not shown for clarity) and M3 (=TM2 or S6) and the M2 pore loop (= P loop). At the M3 helical apex is the ‘helix bundle’ that forms an external ‘gate’ that is mainly lined by residues in the highly conserved SYTANLAAF and regulated by the LILI motif. At the M2 loop apex is the N site (NMDARs) and the Q/R site (AMPARs). c The eukaryotic specific M4 transmembrane helix surrounds the pore domain (M1-M3) with the M4 of one subunit associating with the M1 and M3 of an adjacent subunit. Near the top of the M4 helices are glycines that are conserved across all mammalian iGluR subunits³⁷.