Fig. 1.

Topology of NMDA receptors and distribution of missense mutations in and around the M4 transmembrane segments. a Model NMDAR structure (structure based on 4TLM of GluN1/GluN2B)¹⁶ lacking the intracellular C-terminal domain (CTD). Subunits are colored light orange (GluN1) and gray 60% (GluN2). For iGluRs, the tetrameric complex is composed of four highly modular domains: the extracellularly located amino-terminal (ATD) and ligand-binding (LBD) domains; the membrane-spanning transmembrane domain (TMD) forming the ion channel; and the CTD. Positions highlighted in magenta are disease-associated missense mutations in the GluN1, GluN2A, or GluN2B M4 transmembrane segment or the S2-M4 linker (L812M and I814T in GluN2A). b An enlarged view of the extracellular end of the TMD highlighting the distribution of missense mutations in and around the M4 segments. c The GluN1, GluN2A, and GluN2B M4 segments indicting the specific location of missense mutations. Each dot represents a patient in which the mutation has been identified (Supplementary Table 1). The dashed line separates M3 (leftside) versus lipid (rightside) facing portions of the M4 transmembrane segment