Emerging Models of Glutamate Receptor Ion Channel Structure and Function

Laboratory of Cellular and Molecular Neurophysiology, Porter Neuroscience Research Center, NICHD, NIH, DHHS, Bethesda, MD 20892, USA.
Structure (Impact Factor: 6.79). 10/2011; 19(10):1370-80. DOI: 10.1016/j.str.2011.08.009
Source: PubMed

ABSTRACT Excitatory synaptic transmission in the brain is mediated by ligand-gated ion channels (iGluRs) activated by glutamate. Distinct from other neurotransmitter receptors, the extracellular domains of iGluRs are loosely packed assemblies with two clearly distinct layers, each of which has both local and global 2-fold axes of symmetry. By contrast, the iGluR transmembrane segments have 4-fold symmetry and share a conserved pore loop architecture found in tetrameric voltage-gated ion channels. The striking layered architecture of iGluRs revealed by the 3.6 Å resolution structure of an AMPA receptor homotetramer likely arose from gene fusion events that occurred early in evolution. Although this modular design has greatly facilitated biophysical and structural studies on individual iGluR domains, and suggested conserved mechanisms for iGluR gating, recent work is beginning to reveal unanticipated diversity in the structure, allosteric regulation, and assembly of iGluR subtypes.

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Available from: Mark L Mayer, Aug 26, 2015
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    • "Recent work (Wilding et al. 2014) on chimeric subunits has shown that the GluK2 KA receptor TMD, fused to GluN1 and GluN2B NMDA receptor extracellular domains, is sufficient to recapitulate the modulation observed in homomeric GluK2 receptors, suggesting that cis-unsaturated compounds act directly on the TMD. Because modulation exhibits little or no voltage dependence (Wilding et al. 2005), negatively charged fatty acids are unlikely to enter the pore along the conduction pathway but instead may partition into the membrane and affect channel operation either by altering membrane mechanical properties (Patel et al. 2001; Bruno et al. 2007) or by direct interaction with the TMD, possibly via lateral fenestrations that may expose the pore to membrane constituents (Payandeh et al. 2011; Mayer, 2011). "
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    ABSTRACT: Glutamate receptors are ligand-gated ion channels that mediate fast excitatory synaptic transmission throughout the central nervous system. Functional receptors are homo or heteromeric tetramers with each subunit contributing a re-entrant pore loop that dips into the membrane from the cytoplasmic side. The pore loops form a narrow constriction near their apex with a wide vestibule toward the cytoplasm and an aqueous central cavity facing the extracellular solution. This article focuses on the pore region reviewing how structural differences among glutamate receptor subtypes determine their distinct functional properties.This article is protected by copyright. All rights reserved
    The Journal of Physiology 04/2014; 593(1). DOI:10.1113/jphysiol.2014.272724 · 4.54 Impact Factor
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    • "The a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) subtype ionotropic glutamate receptors (iGluRs) are ligand-gated ion channels that mediate the majority of fast excitatory synaptic transmission in the brain (Traynelis et al., 2010). In common with other iGluRs, each AMPA receptor subunit includes four domains (Mayer, 2011). Closure of the extracellular clamshell-like ligand-binding domains (LBDs) upon glutamate binding is envisaged to open the gate of the cation-permeable ion channel formed by the transmembrane domain (TMD). "
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    ABSTRACT: Ionotropic glutamate receptors (iGluRs) transduce the chemical signal of neurotransmitter release into membrane depolarization at excitatory synapses in the brain. The opening of the transmembrane ion channel of these ligand-gated receptors is driven by conformational transitions that are induced by the association of glutamate molecules to the ligand-binding domains (LBDs). Here, we describe the crystal structure of a GluA2 LBD tetramer in a configuration that involves an ∼30° rotation of the LBD dimers relative to the crystal structure of the full-length receptor. The configuration is stabilized by an engineered disulfide crosslink. Biochemical and electrophysiological studies on full-length receptors incorporating either this crosslink or an engineered metal bridge show that this LBD configuration corresponds to an intermediate state of receptor activation. GluA2 activation therefore involves a combination of both intra-LBD (cleft closure) and inter-LBD dimer conformational transitions. Overall, these results provide a comprehensive structural characterization of an iGluR intermediate state.
    Neuron 08/2013; 79(3):492-503. DOI:10.1016/j.neuron.2013.06.003 · 15.98 Impact Factor
    • "However, direct interactions between odors and IRs, the molecular basis for the observed specificity , and any ligand-induced conformational changes in the LBD (as observed in iGluRs (Mayer, 2011)) remain to be shown. These issues will most likely be best addressed by three-dimensional structural analysis of the IR LBD, a challenging but conceivable goal, given the success in atomic-resolution characterization of this domain in iGluRs (Mayer, 2011). "
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    ABSTRACT: Ionotropic Receptors (IRs) are a recently characterized family of olfactory receptors in the fruit fly, Drosophila melanogaster. IRs are not related to insect Odorant Receptors (ORs), but rather have evolved from ionotropic glutamate receptors (iGluRs), a conserved family of synaptic ligand-gated ion channels. Here, we review the expression and function of IRs in Drosophila, highlighting similarities and differences with iGluRs. We also briefly describe the organization of the neuronal circuits in which IRs function, comparing and contrasting them with the sensory pathways expressing ORs. Finally, we summarize the bioinformatic identification and initial characterization of IRs in other species, which imply an evolutionarily conserved role for these receptors in chemosensation in insects and other protostomes.
    Insect biochemistry and molecular biology 02/2013; 43(9). DOI:10.1016/j.ibmb.2013.02.007 · 3.42 Impact Factor
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