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: 5.62). 10/2011; 19(10):1370-80. DOI: 10.1016/j.str.2011.08.009
Source: PubMed


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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    • "In the mammalian brain, the communication between the PFC and the dorsal/ventral striatum involves the amino acid L-Glutamate (L-Glu) acting through different ionotropic [7] and metabotropic receptors, transduction mechanisms and various modulators [8], [9]. The latter include dopamine (DA), norepinephrine (NE), serotonin (5-HT), and histamine. "
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    ABSTRACT: The cross-talk at the prefronto-striatal interface involves excitatory amino acids, different receptors, transducers and modulators. We investigated long-term effects of a prepuberal, subchronic 5-HT7-R agonist (LP-211) on adult behaviour, amino acids and synaptic markers in a model for Attention-Deficit/Hyperactivity Disorder (ADHD). Naples High Excitability rats (NHE) and their Random Bred controls (NRB) were daily treated with LP-211 in the 5th and 6th postnatal week. One month after treatment, these rats were tested for indices of activity, non selective (NSA), selective spatial attention (SSA) and emotionality. The quantity of L-Glutamate (L-Glu), L-Aspartate (L-Asp) and L-Leucine (L-Leu), dopamine transporter (DAT), NMDAR1 subunit and CAMKIIα, were assessed in prefrontal cortex (PFC), dorsal (DS) and ventral striatum (VS), for their role in synaptic transmission, neural plasticity and information processing. Prepuberal LP-211 (at lower dose) reduced horizontal activity and (at higher dose) increased SSA, only for NHE but not in NRB rats. Prepuberal LP-211 increased, in NHE rats, L-Glu in the PFC and L-Asp in the VS (at 0.250 mg/kg dose), whereas (at 0.125 mg/kg dose) it decreased L-Glu and L-Asp in the DS. The L-Glu was decreased, at 0.125 mg/kg, only in the VS of NRB rats. The DAT levels were decreased with the 0.125 mg/kg dose (in the PFC), and increased with the 0.250 mg/kg dose (in the VS), significantly for NHE rats. The basal NMDAR1 level was higher in the PFC of NHE than NRB rats; LP-211 treatment (at 0.125 mg/kg dose) decreased NMDAR1 in the VS of NRB rats. This study represents a starting point about the impact of developmental 5-HT7-R activation on neuro-physiology of attentive processes, executive functions and their neural substrates.
    Full-text · Article · Apr 2014 · PLoS ONE
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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
    Preview · Article · Apr 2014 · The Journal of Physiology
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    • "The three main iGluR subtypes, named for the agonists N-methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate (KA), are made up of distinct sets of homologous subunits that combine as homo or heteromeric tetramers to form an ion conducting pathway through the membrane1. X-ray crystallography of subunit sub-domains2 and of an intact homomeric AMPA receptor in the closed state3, has revealed a modular structure with 2-fold symmetry in the extracellular amino terminal and ligand binding domains (ATD and LBD) and apparent 4-fold symmetry in the channel-forming transmembrane domain (TMD) (Fig. 1). The iGluR channels exhibit a pore-helix and selectivity filter flanked by two transmembrane helices as originally described for the KcsA channel4, but with inverted topology. "
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    ABSTRACT: Ionotropic glutamate receptors comprise two conformationally different A/C and B/D subunit pairs. Closed channels exhibit fourfold radial symmetry in the transmembrane domain (TMD) but transition to twofold dimer-of-dimers symmetry for extracellular ligand binding and N-terminal domains. Here, to evaluate symmetry in open pores we analysed interaction between the Q/R editing site near the pore loop apex and the transmembrane M3 helix of kainate receptor subunit GluK2. Chimeric subunits that combined the GluK2 TMD with extracellular segments from NMDA receptors, which are obligate heteromers, yielded channels made up of A/C and B/D subunit pairs with distinct substitutions along M3 and/or Q/R site editing status, in an otherwise identical homotetrameric TMD. Our results indicate that Q/R site interaction with M3 occurs within individual subunits and is essentially the same for both A/C and B/D subunit conformations, suggesting that fourfold pore symmetry persists in the open state.
    Preview · Article · Feb 2014 · Nature Communications
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