Glutamate receptors at atomic resolution

Building 35, Room 3B1002, Porter Neuroscience Research Center, 35 Lincoln Drive, Bethesda, Maryland 20892, USA.
Nature (Impact Factor: 41.46). 04/2006; 440(7083):456-62. DOI: 10.1038/nature04709
Source: PubMed


At synapses throughout the brain and spinal cord, the amino-acid glutamate is the major excitatory neurotransmitter. During evolution, a family of glutamate-receptor ion channels seems to have been assembled from a kit consisting of discrete ligand-binding, ion-channel, modulatory and cytoplasmic domains. Crystallographic studies that exploit this unique architecture have greatly aided structural analysis of the ligand-binding core, but the results also pose a formidable challenge, namely that of resolving the allosteric mechanisms by which individual domains communicate and function in an intact receptor.

  • Source
    • "NMDA receptor subunits share a common modular design characterized by: i) an extracellular N-terminal domain (NTD) of about 400 amino acids, which has been implicated in receptor oligomerization, trafficking and modulation; ii) two extracellular segments (S1S2) forming the ligand binding domain (LBD); iii) three transmembrane domains and an intramembrane re-entrant loop, which determines receptor permeation properties; and iv) an intracellular carboxyterminal tail that interacts with postsynaptic scaffolding and signal transduction proteins (Dingledine et al., 1999). Based on structural and functional studies, a mechanistic model for the activation of the conventional NMDA receptor has emerged during the past years (Mayer, 2006;Lee et al., 2014). Accordingly, agonist occupation of both the GluN1 and GluN2 LBDs, which are arranged as hetero-dimers in a 'back-to-back' fashion (Furukawa et al., 2005;Schuler et al., 2008), leads to the closure of both LBDs and thereby generates sufficient conformational strain to initiate channel opening (Furukawa et al., 2005;Inanobe et al., 2005). "
    [Show abstract] [Hide abstract]
    ABSTRACT: N-methyl-d-aspartate (NMDA) receptors composed of glycine-binding GluN1 and GluN3 subunits function as excitatory glycine receptors that respond to agonist application only with a very low efficacy. Binding of glycine to the high-affinity GluN3 subunits triggers channel opening, whereas glycine binding to the low-affinity GluN1 subunits causes an auto-inhibition of the maximal glycine-inducible receptor current (Imax). Hence, competitive antagonists of the GluN1 subunit strongly potentiate glycine responses of wild type (wt) GluN1/GluN3 receptors. Here, we show that co-expression of N-terminal domain (NTD) deleted GluN1 (GluN1ΔNTD) and GluN3 (GluN3ΔNTD) subunits in Xenopus oocytes generates GluN1/GluN3 receptors with a large increase in the glycine-inducible Imax accompanied by a strongly impaired GluN1 antagonist-mediated potentiation. Affinity purification after metabolic or surface labeling revealed no differences in subunit stoichiometry and surface expression between wt GluN1/GluN3A and mutant GluN1ΔNTD/GluN3AΔNTD receptors, indicating a specific effect of NTD deletions on the efficacy of receptor opening. Notably, GluN1/GluN3AΔNTD receptors showed a similar increase in Imax and a greatly reduced GluN1 antagonist-mediated current potentiation as GluN1ΔNTD/GluN3AΔNTD receptors, whereas the glycine-induced currents of GluN1ΔNTD/GluN3A receptors resembled those of wt GluN1/GluN3A receptors. Furthermore, oxidative crosslinking of the homophilic GluN3A NTD intersubunit interface in mutant GluN1/GluN3AR319C receptors caused both a decrease in the glycine-induced Imax concomitantly with a marked increase in GluN1 antagonist-mediated current potentiation, whilst mutations within the intrasubunit region linking the GluN3A NTD to the ligand binding domain had opposite effects. Together these results show that the GluN3A NTD constitutes a crucial regulatory determinant of GluN1/GluN3A receptor function.
    Full-text · Article · Jan 2016 · Neuropharmacology
  • Source
    • "Early evidence favored a pentameric structure for iGluRs based on the sizes of chemically cross-linked proteins and the number of distinct channel activities produced by the mixture of two subunits (Dingledine et al., 1999). However, an overwhelming number of studies analyzing structures, desensitization properties and cross-linking between subunits through cysteines now suggest that mammalian iGluRs assemble as tetramers (reviewed in Mayer, 2006; Traynelis et al., 2010). In mammals, functional ligand-gated channels can be formed from either homo-or heteromers of four subunits within the same agonist class (Rosenmund et al., 1998). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The plant glutamate-like receptor homologs (GLRs) are homologs of mammalian ionotropic glutamate receptors (iGluRs) which were discovered more than 10 years ago, and are hypothesized to be potential amino acid sensors in plants. Although initial progress on this gene family has been hampered by gene redundancy and technical issues such as gene toxicity; genetic, pharmacological, and electrophysiological approaches are starting to uncover the functions of this protein family. In parallel, there has been tremendous progress in elucidating the structure of animal glutamate receptors (iGluRs), which in turn will help understanding of the molecular mechanisms of plant GLR functions. In this review, we will summarize recent progress on the plant GLRs. Emerging evidence implicates plant GLRs in various biological processes in and beyond N sensing, and implies that there is some overlap in the signaling mechanisms of amino acids between plants and animals. Phylogenetic analysis using iGluRs from metazoans, plants, and bacteria showed that the plant GLRs are no more closely related to metazoan iGluRs as they are to bacterial iGluRs, indicating the separation of plant, other eukaryotic, and bacterial GLRs might have happened as early on as the last universal common ancestor. Structural similarities and differences with animal iGluRs, and the implication thereof, are also discussed.
    Preview · Article · Oct 2012 · Frontiers in Plant Science
  • Source
    • "The long extracellular N-terminal regions of NMDAR subunits are organized as a tandem of two domains. The first domain, called the N-terminal domain (NTD) that includes the first 380 amino acids, is involved in tetrameric assembly (Mayer, 2006; Paoletti and Neyton, 2007; Stroebel et al., 2011). The second domain of about 300 amino acids is known as the agonist-binding domain (ABD) that precedes the TM1 domain. "
    [Show abstract] [Hide abstract]
    ABSTRACT: N-methyl-D-aspartate receptors (NMDARs) are glutamate-gated ion channels highly permeable to calcium and essential to excitatory neurotransmission. The NMDARs have attracted much attention because of their role in synaptic plasticity and excitotoxicity. Evidence has recently accumulated that NMDARs are negatively regulated by intracellular calcium binding proteins. The calcium-dependent suppression of NMDAR function serves as a feedback mechanism capable of regulating subsequent Ca(2+) entry into the postsynaptic cell, and may offer an alternative approach to treating NMDAR-mediated excitotoxic injury. This short review summarizes the recent progress made in understanding the negative modulation of NMDAR function by DREAM/calsenilin/KChIP3, a neuronal calcium sensor (NCS) protein.
    Preview · Article · Apr 2012 · Frontiers in Molecular Neuroscience
Show more