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.

Download full-text


Available from: Mark L Mayer,
  • 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.
    Frontiers in Plant Science 10/2012; 3:235. DOI:10.3389/fpls.2012.00235 · 3.95 Impact Factor
  • 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.
    Frontiers in Molecular Neuroscience 04/2012; 5:39. DOI:10.3389/fnmol.2012.00039 · 4.08 Impact Factor
  • Source
    • "Based on sequence homology and pharmacology, iGluRs can be grouped into three main subfamilies: AMPA-, kainate- and NMDA-type, the latter being unique in its ability to flux calcium and trigger synaptic plasticity mechanisms [1]. Since the cloning of iGluR subunits some twenty years ago, a wealth of information regarding iGluR structure and mechanism of operation has been obtained [2], [3]. Unlike other ionotropic neurotransmitter receptors that form either pentamers (Cys-loop receptors) or trimers (P2X receptors), the iGluRs assemble as tetrameric complexes composed of four homologous pore-forming subunits. "
    [Show abstract] [Hide abstract]
    ABSTRACT: NMDA receptors (NMDARs) form glutamate-gated ion channels that play a critical role in CNS physiology and pathology. Together with AMPA and kainate receptors, NMDARs are known to operate as tetrameric complexes with four membrane-embedded subunits associating to form a single central ion-conducting pore. While AMPA and some kainate receptors can function as homomers, NMDARs are obligatory heteromers composed of homologous but distinct subunits, most usually of the GluN1 and GluN2 types. A fundamental structural feature of NMDARs, that of the subunit arrangement around the ion pore, is still controversial. Thus, in a typical NMDAR associating two GluN1 and two GluN2 subunits, there is evidence for both alternating 1/2/1/2 and non-alternating 1/1/2/2 arrangements. Here, using a combination of electrophysiological and cross-linking experiments, we provide evidence that functional GluN1/GluN2A receptors adopt the 1/2/1/2 arrangement in which like subunits are diagonal to one another. Moreover, based on the recent crystal structure of an AMPA receptor, we show that in the agonist-binding and pore regions, the GluN1 subunits occupy a "proximal" position, closer to the central axis of the channel pore than that of GluN2 subunits. Finally, results obtained with reducing agents that differ in their membrane permeability indicate that immature (intracellular) and functional (plasma-membrane inserted) pools of NMDARs can adopt different subunit arrangements, thus stressing the importance of discriminating between the two receptor pools in assembly studies. Elucidating the quaternary arrangement of NMDARs helps to define the interface between the subunits and to understand the mechanism and pharmacology of these key signaling receptors.
    PLoS ONE 04/2012; 7(4):e35134. DOI:10.1371/journal.pone.0035134 · 3.23 Impact Factor
Show more