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Review
. 2015 Jun;40(6):328-37.
doi: 10.1016/j.tibs.2015.04.002. Epub 2015 May 1.

Emerging structural insights into the function of ionotropic glutamate receptors

Erkan Karakas  1 , Michael C Regan  1 , Hiro Furukawa  2
Affiliations
Review

Emerging structural insights into the function of ionotropic glutamate receptors

Erkan Karakas et al. Trends Biochem Sci. 2015 Jun.

Abstract

Ionotropic glutamate receptors (iGluRs) are ligand-gated ion channels that mediate excitatory neurotransmission crucial for brain development and function, including learning and memory formation. Recently a wealth of structural studies on iGluRs including AMPA receptors (AMPARs), kainate receptors, and NMDA receptors (NMDARs) became available. These studies showed structures of non-NMDARs including AMPAR and kainate receptor in various functional states, thereby providing the first visual sense of how non-NMDAR iGluRs may function in the context of homotetramers. Furthermore, they provided the first view of heterotetrameric NMDAR ion channels, and this illuminated the similarities with and differences from non-NMDARs, thus raising a mechanistic distinction between the two groups of iGluRs. We review mechanistic insights into iGluR functions gained through structural studies of multiple groups.

Keywords: ionotropic glutamate receptors; pharmacology; structural biology.

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Figures

Figure 1
Figure 1. Domain organization and subunit arrangement of iGluRs
(A) The ionotropic glutamate receptor subunits are composed of distinct domains including the amino terminal domain (ATD), ligand-binding domain (LBD), transmembrane domain (TMD), and carboxyl terminal domain (CTD). The TMD of one subunit is composed of M1-M4 helices. Schematic representation of tetrameric subunit organization of non-NMDARs (B) and NMDARs (C) at ATD, LBD and TMD layers are shown. Dimer pairs at ATD and LBD are indicated by lack of black lines at the interface. The four subunits in non-NMDARs are noted as A-D.
Figure 2
Figure 2. Structures of GluA2 AMPAR and GluK2 kainate receptors in various functional states
Surface representation of the structures in ligand-free (A), antagonist-bound closed (B), agonist and allosteric modulator-bound pre-open (C) and agonist-bound (D) and agonist-bound desensitized (E) states are shown as viewed from the side for the whole receptor (left) and from top for the LBD tetramer (right). Ligand combinations used and PDB IDs for the structures are shown for each structure (Table 1). Subunits are colored as yellow, cyan, magenta and blue for the subunits A,B,C and D, respectively. The con-ikot-ikot toxin molecule in panel C is colored in grey.
Figure 3
Figure 3. Structural changes in the gating ring during receptor activation of non-NMDARs
LBD tetramers of antagonist-bound (PDB ID: 3KG2) (A), FW/(R,R)-2b-bound (PDB ID: 4U1Y) (B) and, FW/(R,R)-2b-bound and con-ikot-ikot toxin-bound (PDB ID: 4U5C) (C) GluA2 receptors are shown in ribbon representation and viewed from the top of the receptor. Distances between Cα atoms (black spheres) of Arg660 from A/C subunits, and Gln756 from B/D subunits are measured and plotted (D) along with the distances for GluA2 structures in other conformations. The distances for NMDARs are measured between Arg694 for GluN1 (chain A/C) and Asp786 for GluN2B (chain B/D). The distances for kainate receptors are measured between Lys664 for A/C subunits and Glu757 for B/D subunits.
Figure 4
Figure 4. Conformational changes at the LBD-TM3 linker during receptor activation
Helices E on the LBD and TM3 at the TMD of B/D subunits (panels A and C) and A/C subunits (panels B and D) are viewed from side (panels A and B) and top (panels C and D). (E) Plot of the istances between Cα atoms (spheres) of Ala636 and Thr625 within the same subunits for apo, FW and (R,R)-2b bound, FW, (R,R)-2b and toxin bound, and ZK200775 bound structures along with the distances for GluA2 structures in other conformations. Distances between Val656 and Ile667 for NMDAR GluN1 subunit, Ile655 and Leu666 for NMDAR GluN2B subunit and Thr629 and Ala640 for kainate receptors are also plotted in (E). The values for the plot are averages of the distances of A/C subunits or B/D subunits.
Figure 5
Figure 5. Comparison of the intact GluN1/GluN2B NMDAR and GluA2 AMPAR structures
(A). Both the NMDAR and non-NMDARs consist of four distinct domains: the extra cellular ATD and LBD, the TMD, and a long, largely unstructured Carboxyl Terminal Domain (not shown). The AMPAR assumes a domain-swapped assembly similar to the NMDAR, but with a more extended conformation leading to substantially less interaction between the ATD and LBD. (B). The ATD dimers in particular show dramatically different interactions between the subunits in the AMPAR (and Kainate receptor) vs NMDAR.
Figure 6
Figure 6. Heterotetrameric GluN1/GluN2B NMDAR and small molecule binding sites
Numerous ligands have been identified that influence NMDAR activity. Co-agonists glycine [76] and glutamate bind at the LBD of the GluN1 and GluN2 subunits, respectively [77]. The small molecule PYD-106 is a GluN2C-specific allosteric activator which binds at the ATD/LBD interface [70]. Polyamines such as spermine and spermidine bind at the interface of two ATDs in GluN2B-containing receptors and potentiate channel activity [78], but only in GluN1 isoforms lacking Exon5 [79]. A number of NMDAR inhibitors have also been identified, including extracellular Zn2+ [53] binding at the hinge region of the GluN2 ATD [26] (and with a notably stronger effect on GluN2A-containing receptors over other types), and voltage-dependent block by Mg2+ at the TMD [68]. Phenylethanolamines, such as ifenprodil, bind at the interface of the GluN1/GluN2B ATDs [27], while the inhibitor MK-801 is purported to bind very near to the center of the ion channel [54]. A sequence of acidic residues in the LBD/TMD M3 linker in the GluN1 subunit known as the DRPEER motif is essential for calcium binding and conductance [53].
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