Structure of the tetrameric ionotropic glutamate receptor. A, ionotropic glutamate receptor subunits possesses a modular structure with four distinct semiautonomous domains that include the extracellular ATD, the extracellular ligand binding domain (LBD), the transmembrane domain (TMD), and an intracellular carboxyl-terminal domain. B, structure of the membrane-spanning tetrameric GluA2 AMPA receptor [Protein Data Bank (PDB) code 3KG2]. Peptide linkers that connect the semiautonomous domains are shown as gray spheres. C, glutamate receptors have two conformationally distinct subunits within the tetrameric receptor, which have been denoted A/C-type and B/D-type subunits. D, the extracellular ATDs and ligand binding domains are organized as dimer of dimers with approximately 2-fold symmetry, whereas the pore-forming transmembrane domain is organized with 4-fold symmetry. The A-type subunit forms an ATD dimer with the B-type subunit, but the ligand binding domain of the A-type subunit forms a ligand binding domain dimer with the D-type subunit. The “subunit crossover” creates an opportunity for both extensive intersubunit as well as intrasubunit interactions that involve the ATD.

The NMDA receptor subunit GluN2 ATD influence agonist potency. Exchange of the ATD between GluN2A and GluN2D, two subunits with the most divergent properties, shifts the potency of glutamate in the direction of the subunit contributing the ATD. The chimeric GluN2A-(2D ATD) is GluN2A with the ATD replaced by the ATD of GluN2D, and GluN2D-(2A ATD) is GluN2D with the ATD replaced by the ATD of GluN2A. The glutamate potency at GluN2A-(2D ATD) is similar to that of wild-type GluN2D, and the potency of GluN2D-(2A ATD) is similar to that of wild-type GluN2A. Wild-type and chimeric GluN2 subunits were coexpressed with GluN1 in Xenopus laevis oocytes and glutamate potencies were determined by two-electrode voltage-clamp electrophysiology. See also Fig. 4. Data are from Yuan et al. (2009a).

Structures for noncompetitive NMDA receptor antagonists acting at the GluN2B ATD. See Table 1 for IC₅₀ values for inhibition of NMDA receptor subtypes by these ligands. The threo-ifenprodil stereoisomers, one of which is shown, appear more potent than erythro-ifenprodil isomers (Chenard et al., 1991).

Structures of ionotropic glutamate receptor ATDs. A, structure of the AMPA receptor GluA2 ATD dimer (PDB code 3H5V). The ATD structure adopts a bilobed structure composed of two halves, referred to as R1 (distal to the membrane) and R2 (proximal to the membrane), with extensive intersubunit R1-R1 and R2-R2 contacts. The N terminus is located at the top of the R1 lobe, whereas the bottom of the R2 lobe connects to the ligand binding domain through the ATD-S1 linker. B, the structure of the kainate receptor GluK2 ATD (PDB code 3H6G) is similar to that of the GluA2 ATD. C, the GluN2B ATD is also a clamshell-like bilobed structure composed of two halves (R1 in blue and R2 in yellow) (PDB code 3JPY). D, structural alignment of the ATD structures from GluN2B and non-NMDA receptors (GluA2/GluK2). The GluN2B ATD has a structural fold similar to that of non-NMDA receptor ATDs but with a strikingly different conformation. The position of the R1 lobe in the GluN2B ATD is rotated ∼50° relative to the R2 lobe compared with the ATDs from AMPA and kainate receptors. This “twisted” R1-R2 orientation of GluN2B ATD results from the lack of a helix-loop motif present in both AMPA and kainate receptors, which hold R1 and R2 lobes together in a “nontwisted” configuration. E, evaluation of the GluN2B ATD structure reveals possible modulatory binding sites. The cleft between the R1 and R2 lobes contains a hydrophilic pocket with polar residues that participate in Zn²⁺ coordination, a hydrophobic pocket that resides deeper in the cleft containing some (but not all) residues critical for activity of the GluN2B-selective antagonist ifenprodil, and an ion binding site that accommodates one Na⁺ and three Cl⁻ ions. Density for Zn²⁺ is represented by anomalous difference Fourier map at 6 σ whereas that for Na⁺ and Cl⁻ is represented by F_o − F_c omit map at 5.5 σ.

The NMDA receptor subunit GluN2 ATD influences open probability. Exchange of the ATD between GluN2A and GluN2D shifts the open probability in the direction of the subunit contributing the ATD without changing the channel conductance. Replacement of the GluN2A ATD with that of GluN2D decreases open probability and mean open duration. By contrast, replacement of the GluN2D ATD with that of GluN2A increases open probability and mean open duration. Wild-type and chimeric GluN2 subunits were coexpressed with GluN1 in human embryonic kidney cells and characterized by recordings from single channels in outside-out patches in the presence of saturating glutamate and glycine. See also Fig. 3. [Reproduced from Yuan H, Hansen KB, Vance KM, Ogden KK, and Traynelis SF (2009) Control of NMDA receptor function by the NR2 subunit amino-terminal domain. J Neurosci 29:12045–12058. Copyright © 2009 The Society for Neuroscience. Used with permission.]