Figure 1.

Structure of NMDA receptor. NMDAR is a tetramer comprised of two NR1 and two NR2 subunits. This 3D schematic shows a cross-section of the NMDAR through the channel pore. The NMDAR is composed of four domains: amino terminal domain (ATD), agonist binding domain, transmembrane domain and intracellular C-terminal domain (not shown). The NR1 subunit binds glycine or d-serine and the NR2A/B subunit binds glutamate. Activation of the NMDAR requires binding of both glycine (or d-serine) and glutamate, as well as simultaneous depolarization of the ion channel by AMPA or kainate receptors, which relieves the Mg²⁺ block. Under these conditions, the NMDAR channel will open and permit the entry of both Na⁺ and Ca²⁺ and the exit of K⁺. Within the ion channel, two additional binding sites have been identified: the sigma (σ) site (holding Mg²⁺) and the phencyclidine (PCP) site. The hallucinogenic drug PCP and ketamine, bind the PCP site and are considered noncompetitive receptor antagonists, which inhibit NMDAR channel function. Several other endogenous ligands interact with the NMDAR at different sites on the molecule and can have modulatory effects on its function. The endogenous polyamine spermine interacts with the NR2B subunit of the NMDAR and potentiates channel opening; paradoxically, it (and other polyamines) can also block the channel, reducing its conductance. Zinc also inhibits the NMDAR in a subtype-specific manner; receptors containing NR2A are inhibited by far lower concentrations of zinc than are those containing NR2B. Receptor activity is also modulated, at least in vitro, by redox state and pH. The 3D structure was cited from Dr Huggins' article [55].