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Shigetada Nakanishi - One of the best experts on this subject based on the ideXlab platform.

  • Structure of the metabotropic Glutamate Receptor.
    Current Opinion in Neurobiology, 2003
    Co-Authors: Hisato Jingami, Shigetada Nakanishi, Kosuke Morikawa
    Abstract:

    Abstract In the twelve years since the molecular elucidation of the metabotropic Glutamate Receptor subtype 1, a class III family of G-protein-coupled Receptors has emerged; members of this family include the calcium-sensing Receptor, the GABA B Receptor, some odorant Receptors and some taste Receptors. Atomic structures of the ligand-binding core of the original metabotropic Glutamate Receptor 1 obtained using X-ray crystallography provide a foundation for determining the initial Receptor activation of this important family of G-protein-coupled Receptors.

  • induction of an olfactory memory by the activation of a metabotropic Glutamate Receptor
    Science, 1994
    Co-Authors: Hideto Kaba, Takashi Higuchi, Yasunori Hayashi, Shigetada Nakanishi
    Abstract:

    Female mice form an olfactory memory of male pheromones at mating; exposure to the pheromones of a strange male after that mating will block pregnancy. The formation of this memory is mediated by the accessory olfactory system, in which an increase in norepinephrine after mating reduces inhibitory transmission of gamma-aminobutyric acid from the granule cells to the mitral cells. This study shows that the activation of mGluR2, a metabotropic Glutamate Receptor that suppresses the gamma-aminobutyric acid inhibition of the mitral cells, permits the formation of a specific olfactory memory without the occurrence of mating by infusion of mGluR2 agonists into the female9s accessory olfactory bulb. This memory faithfully reflects the memory formed at mating.

  • molecular characterization of a novel metabotropic Glutamate Receptor mglur5 coupled to inositol phosphate ca2 signal transduction
    Journal of Biological Chemistry, 1992
    Co-Authors: Hidemitsu Sugihara, Ryuichi Shigemoto, Hiroyuki Nawa, Noboru Mizuno, Shigetada Nakanishi
    Abstract:

    Abstract A cDNA clone for a new metabotropic Glutamate Receptor, mGluR5, was isolated through polymerase chain reaction-mediated DNA amplification by using primer sequences conserved among the metabotropic Glutamate Receptor (mGluR) family and by the subsequent screening of a rat brain cDNA library. The cloned Receptor consists of 1171 amino acid residues and exhibits a structural architecture common to the mGluR family, possessing a large extracellular domain preceding the seven putative membrane-spanning segments. mGluR5 shows the highest sequence similarity to mGluR1 among the mGluR members and is coupled to the stimulation of phosphatidylinositol hydrolysis/Ca2+ signal transduction in Chinese hamster ovary cells transfected with the cloned cDNA. This Receptor also resembles mGluR1 in its agonist selectivity and antagonist responses; the potency rank order of agonists for mGluR5 was determined to be quisqualate greater than L-Glutamate greater than or equal to ibotenate greater than trans-1-aminocyclopentane-1,3-dicarboxylate. Blot and in situ hybridization analyses indicated that mGluR5 mRNA is widely distributed in neuronal cells of the central nervous system and is expressed differently from mGluR1 mRNA in many brain regions. This investigation thus demonstrates that there is an additional mGluR subtype which closely resembles mGluR1 in its signal transduction and pharmacological properties and is expressed in specialized neuronal cells in the central nervous system.

  • signal transduction and pharmacological characteristics of a metabotropic Glutamate Receptor mglurl in transfected cho cells
    Neuron, 1992
    Co-Authors: Ichiro Aramori, Shigetada Nakanishi
    Abstract:

    Abstract The signal transduction and pharmacological properties of a metabotropic Glutamate Receptor, mGluR1, were studied in CHO cells permanently expressing the cloned Receptor. mGluR1 stimulated phosphatidylinositol (PI) hydrolysis in the potency rank order of quisqualate> l -Glutamate ⩾ ibotenate> l -homocysteine sulfinate ⩾trans-ACPD. This Receptor also evoked the stimulation of cAMP formation and arachidonic acid release with comparable agonist potencies. dl -AP3 and l -AN4, the effective antagonists reported for Glutamate-stimulated PI hydrolysis in brain slices, showed no appreciable effects on mGIuR1, suggesting the existence of an additional subtype of this Receptor family. Pertussis toxin and phorbol ester produced distinct effects on the three transduction cascades, implying that mGIuR1 independently links to the multiple transduction pathways probably through different G proteins.

  • sequence and expression of a metabotropic Glutamate Receptor
    Nature, 1991
    Co-Authors: Masayuki Masu, Yasuto Tanabe, Kunihiro Tsuchida, Ryuichi Shigemoto, Shigetada Nakanishi
    Abstract:

    The complementary DNA of a metabotropic Glutamate Receptor coupled to inositol phosphate/Ca2+ signal transduction has been cloned and characterized. This Receptor shows no sequence similarity to conventional G protein-coupled Receptors and has a unique structure with large hydrophilic sequences at both sides of seven putative membrane-spanning domains. Abundant expression of this messenger RNA is observed in neuronal cells in hippocampal dentate gyrus and CA2−3 and in cerebellar Purkinje cells, suggesting the importance of this Receptor in specific hippocampal and cerebellar functions.

Eric Gouaux - One of the best experts on this subject based on the ideXlab platform.

  • x ray structure symmetry and mechanism of an ampa subtype Glutamate Receptor
    Nature, 2009
    Co-Authors: Alexander I. Sobolevsky, Eric Gouaux, Michael P Rosconi
    Abstract:

    Ionotropic Glutamate Receptors mediate most excitatory neurotransmission in the central nervous system and function by opening a transmembrane ion channel upon binding of Glutamate. Despite their crucial role in neurobiology, the architecture and atomic structure of an intact ionotropic Glutamate Receptor are unknown. Here we report the crystal structure of the α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-sensitive, homotetrameric, rat GluA2 Receptor at 3.6 A resolution in complex with a competitive antagonist. The Receptor harbours an overall axis of two-fold symmetry with the extracellular domains organized as pairs of local dimers and with the ion channel domain exhibiting four-fold symmetry. A symmetry mismatch between the extracellular and ion channel domains is mediated by two pairs of conformationally distinct subunits, A/C and B/D. Therefore, the stereochemical manner in which the A/C subunits are coupled to the ion channel gate is different from the B/D subunits. Guided by the GluA2 structure and site-directed cysteine mutagenesis, we suggest that GluN1 and GluN2A NMDA (N-methyl-d-aspartate) Receptors have a similar architecture, with subunits arranged in a 1-2-1-2 pattern. We exploit the GluA2 structure to develop mechanisms of ion channel activation, desensitization and inhibition by non-competitive antagonists and pore blockers. Most of the excitatory neurotransmissions in the central nervous system, the events that allow neurons to 'talk' to each other, are mediated by ionotropic Glutamate Receptors that act by opening a transmembrane ion channel on binding Glutamate. Little was known about their overall structure, but now Eric Gouaux and colleagues report the crystal structure of the homotetrameric AMPA-subtype rat GluA2 Receptor bound to a competitive antagonist. The structure reveals a novel symmetry arrangement requiring two of the four subunits to adopt a different shape from the other two. This means that Glutamate binding, and ensuing channel opening, is not the same for each subunit. The structure, taken with data from crystallographic and site-directed mutagenesis experiments, suggests that other Glutamate Receptor subtypes, including kainate and NMDA, have similar overall architectures and molecular symmetries. Mechanisms of ion channel activation, desensitization and inhibition by non-competitive antagonists and pore blockers can be inferred from this structure. The majority of excitatory neurotransmission in the central nervous system is mediated by ionotropic Glutamate Receptors, which function by opening a transmembrane ion channel upon binding of Glutamate. However, despite this crucial role in neurobiology, the architecture and atomic structure of an intact isotropic Glutamate Receptor are unknown. The X-ray crystal structure of the rat GluA2 Receptor in complex with a competitive antagonist is now reported and analysed.

  • mechanism of Glutamate Receptor desensitization
    Nature, 2002
    Co-Authors: Rich Olson, M Horning, N Armstrong, Mark L Mayer, Eric Gouaux
    Abstract:

    Ligand-gated ion channels transduce chemical signals into electrical impulses by opening a transmembrane pore in response to binding one or more neurotransmitter molecules. After activation, many ligand-gated ion channels enter a desensitized state in which the neurotransmitter remains bound but the ion channel is closed. Although Receptor desensitization is crucial to the functioning of many ligand-gated ion channels in vivo, the molecular basis of this important process has until now defied analysis. Using the GluR2 AMPA-sensitive Glutamate Receptor, we show here that the ligand-binding cores form dimers and that stabilization of the intradimer interface by either mutations or allosteric modulators reduces desensitization. Perturbations that destabilize the interface enhance desensitization. Receptor activation involves conformational changes within each subunit that result in an increase in the separation of portions of the Receptor that are linked to the ion channel. Our analysis defines the dimer interface in the resting and activated state, indicates how ligand binding is coupled to gating, and suggests modes of dimer–dimer interaction in the assembled tetramer. Desensitization occurs through rearrangement of the dimer interface, which disengages the agonist-induced conformational change in the ligand-binding core from the ion channel gate.

Stephen F Traynelis - One of the best experts on this subject based on the ideXlab platform.

  • Glutamate Receptor gating.
    Critical Reviews in Neurobiology, 2020
    Co-Authors: Kevin Erreger, Philip E. Chen, David J. A. Wyllie, Stephen F Traynelis
    Abstract:

    : Ionotropic Glutamate Receptors (iGluRs) mediate the vast majority of fast excitatory synaptic transmissions within the mammalian central nervous system (CNS). As for other ion channel protein families, there has been astounding progress in recent years in elucidating the details of protein structure through the crystallization of at least part of the ion channel protein complex. The result is a new framework for the interpretation of both classic and emerging functional data. Here we summarize, compare, and contrast recent findings for the AMPA, kainate, and NMDA subtypes of Glutamate Receptor ion channels, with an emphasis on the functional and structural aspects of how agonist binding controls channel gating.

  • ionotropic gaba and Glutamate Receptor mutations and human neurologic diseases
    Molecular Pharmacology, 2015
    Co-Authors: Hongjie Yuan, Olivia A Moody, Andrew Jenkins, Stephen F Traynelis
    Abstract:

    The advent of whole exome/genome sequencing and the technology-driven reduction in the cost of next-generation sequencing as well as the introduction of diagnostic-targeted sequencing chips have resulted in an unprecedented volume of data directly linking patient genomic variability to disorders of the brain. This information has the potential to transform our understanding of neurologic disorders by improving diagnoses, illuminating the molecular heterogeneity underlying diseases, and identifying new targets for therapeutic treatment. There is a strong history of mutations in GABA Receptor genes being involved in neurologic diseases, particularly the epilepsies. In addition, a substantial number of variants and mutations have been found in GABA Receptor genes in patients with autism, schizophrenia, and addiction, suggesting potential links between the GABA Receptors and these conditions. A new and unexpected outcome from sequencing efforts has been the surprising number of mutations found in Glutamate Receptor subunits, with the GRIN2A gene encoding the GluN2A N-methyl-d-aspartate Receptor subunit being most often affected. These mutations are associated with multiple neurologic conditions, for which seizure disorders comprise the largest group. The GluN2A subunit appears to be a locus for epilepsy, which holds important therapeutic implications. Virtually all α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid Receptor mutations, most of which occur within GRIA3, are from patients with intellectual disabilities, suggesting a link to this condition. Similarly, the most common phenotype for kainate Receptor variants is intellectual disability. Herein, we summarize the current understanding of disease-associated mutations in ionotropic GABA and Glutamate Receptor families, and discuss implications regarding the identification of human mutations and treatment of neurologic diseases.

  • Glutamate Receptor ion channels structure regulation and function
    Pharmacological Reviews, 2010
    Co-Authors: Stephen F Traynelis, Scott J. Myers, Lonnie P Wollmuth, Chris J Mcbain, Frank S Menniti, Katie M Vance, Kevin K Ogden, Kasper B Hansen, Hongjie Yuan, Raymond Dingledine
    Abstract:

    The mammalian ionotropic Glutamate Receptor family encodes 18 gene products that coassemble to form ligand-gated ion channels containing an agonist recognition site, a transmembrane ion permeation pathway, and gating elements that couple agonist-induced conformational changes to the opening or closing of the permeation pore. Glutamate Receptors mediate fast excitatory synaptic transmission in the central nervous system and are localized on neuronal and non-neuronal cells. These Receptors regulate a broad spectrum of processes in the brain, spinal cord, retina, and peripheral nervous system. Glutamate Receptors are postulated to play important roles in numerous neurological diseases and have attracted intense scrutiny. The description of Glutamate Receptor structure, including its transmembrane elements, reveals a complex assembly of multiple semiautonomous extracellular domains linked to a pore-forming element with striking resemblance to an inverted potassium channel. In this review we discuss International Union of Basic and Clinical Pharmacology Glutamate Receptor nomenclature, structure, assembly, accessory subunits, interacting proteins, gene expression and translation, post-translational modifications, agonist and antagonist pharmacology, allosteric modulation, mechanisms of gating and permeation, roles in normal physiological function, as well as the potential therapeutic use of pharmacological agents acting at Glutamate Receptors.

  • the Glutamate Receptor ion channels
    Pharmacological Reviews, 1999
    Co-Authors: Raymond Dingledine, Karin Borges, Derek Bowie, Stephen F Traynelis
    Abstract:

    The ionotropic Glutamate Receptors are ligand-gated ion channels that mediate the vast majority of excitatory neurotransmission in the brain. The cloning of cDNAs encoding Glutamate Receptor subunits, which occurred mainly between 1989 and 1992 ([Hollmann and Heinemann, 1994][1]), stimulated this

Stephen F Heinemann - One of the best experts on this subject based on the ideXlab platform.

  • identification of a site in Glutamate Receptor subunits that controls calcium permeability
    Science, 1991
    Co-Authors: Richard I Hume, Raymond Dingledine, Stephen F Heinemann
    Abstract:

    The neurotransmitter Glutamate mediates excitatory synaptic transmission throughout the brain. A family of genes encoding subunits of the non-N-methyl-D-aspartate (non-NMDA) type of Glutamate Receptor has been cloned. Some combinations of these subunits assemble into Receptors with a substantial permeability to calcium, whereas others do not. To investigate the structural features that control ion permeation through these ligand-gated channels, mutant Receptor subunits with single-amino acid changes were constructed. Mutation of a certain amino acid that results in a net charge change (from glutamine to arginine or vice versa) alters both the current-voltage relation and the calcium permeability of non-NMDA Receptors. A site has thus been identified that regulates the permeation properties of these Glutamate Receptors.

  • cloning of a cdna for a Glutamate Receptor subunit activated by kainate but not ampa
    Nature, 1991
    Co-Authors: Jan Egebjerg, Bernhard Bettler, Irm Hermansborgmeyer, Stephen F Heinemann
    Abstract:

    FAST excitatory transmission in the vertebrate central nervous system is mediated mainly by L-Glutamate. On the basis of pharmacological, physiological and agonist binding properties, the ionotropic Glutamate Receptors are classified into NMDA (N-methyl-D-aspartate), AMPA (α-amino-3-hydroxy-5-methyl-isoxazoIe-4-propionate) and kainate subtypes1. Sequence homology between complementary DNA clones encoding non-NMDA Glutamate Receptor subunits reveals at least two subunit classes: the GluRl to GluR4 class2–6 and the GluRS class7. Here we report the cloning and expression of a functional rat Glutamate Receptor subunit cDNA, GluR6, which has a very different pharmacology from that of the GluRl–GluR4 class. Receptors generated from the GluRl-GluR4 class have a higher apparent affinity for AMPA than for kainate3–6. When expressed in Xenopus oocytes the homomeric GluR6 Receptor is activated by kainate, quisqualate and L-Glutamate but not by AMPA, and the apparent affinity for kainate is higher than for Receptors from the GluRl–GluR4 class. Desensitization of the Receptor was observed with continuous application of agonist. The homomeric GluR6 Glutamate Receptor exhibits an outwardly rectifying current–voltage relationship. In situ hybridizations reveal a pattern of GluR6 gene expression reminiscent of the binding pattern obtained with [3H]kainate.

  • ca2 permeability of ka ampa gated Glutamate Receptor channels depends on subunit composition
    Science, 1991
    Co-Authors: Michael Hollmann, M Hartley, Stephen F Heinemann
    Abstract:

    NMDA (N-methyl-D-aspartate) Receptors and non-NMDA Receptors represent the two major classes of ion channel-linked Glutamate Receptors. Unlike the NMDA Receptor channels, non-NMDA Receptor channels have usually been thought to conduct monovalent cations only. Non-NMDA Receptor ion channels that can be gated by kainic acid (KA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) are formed by the Glutamate Receptor subunits GluR1, GluR2, and GluR3. These subunits were expressed in various combinations in Xenopus oocytes so that their permeability to divalent cations could be studied. At physiological resting potentials, KA and AMPA elicited inward calcium currents in oocytes expressing GluR1, GluR3, and GluR1 plus GluR3. In contrast, oocytes expressing GluR1 plus GluR2 or GluR3 plus GluR2 showed no such permeability. Thus, in neurons expressing certain KA-AMPA Receptor subunits, Glutamate may trigger calcium-dependent intracellular events by activating non-NMDA Receptors.

  • cloning of a novel Glutamate Receptor subunit glur5 expression in the nervous system during development
    Neuron, 1990
    Co-Authors: Bernhard Bettler, Irm Hermansborgmeyer, Michael Hollmann, Anne Osheagreenfield, Jim Boulter, Evan S Deneris, Carl Moll, Uwe Borgmeyer, Stephen F Heinemann
    Abstract:

    Abstract We have isolated cDNAs encoding a Glutamate Receptor subunit, designated GluR5, displaying 40%–41% amino acid identity with the kainate/AMPA Receptor subunits GluR1, GIuR2, GIuR3, and GIuR4. This level of sequence similarity is significantly below the approximately 70% intersubunit identity characteristic of kainate/AMPA Receptors. The GIuR5 protein forms homomeric ion channels in Xenopus oocytes that are weakly responsive to L-Glutamate. The GIuR5 gene is expressed in subsets of neurons throughout the developing and adult central and peripheral nervous systems. During embryogenesis, GluR5 transcripts are detected in areas of neuronal differentiation and synapse formation.

Karin N. Westlund - One of the best experts on this subject based on the ideXlab platform.

  • ultrastructural localization of Glutamate Receptor subunits nmdar1 ampa glur1 and glur2 3 and spinothalamic tract cells
    Neuroreport, 1996
    Co-Authors: Zaiming Ye, Karin N. Westlund
    Abstract:

    : The associations of Glutamate Receptor subunits (NMDAR1, AMPA GluR1 and GluR2/3) and spinothalamic tract neurons in the rat lumbar spinal cord dorsal horn were investigated. Staining for NMDAR1 and AMPA GluR1 and GluR2/3 Receptor subunits was observed throughout the spinothalamic tract soma and dendrites, particularly in association with the rough endoplasmic reticulum and some postsynaptic membrane sites. Immunostaining for NMDAR1 and AMPA GluR2/3 was also noted in presynaptic membrane sites. Localization of both NMDA and AMPA Glutamate Receptor subunits in association with spinothalamic tract neurons provides anatomical evidence in support of the various interactions reported for Glutamate Receptors in nociception. Presynaptic localization of the AMPA GluR2/3 Receptor subunit suggests that spinothalamic tract cells may also be affected presynaptically by AMPA Glutamate Receptor interactions.

  • Ultrastructural localization of Glutamate Receptor subunits (NMDAR1, AMPA GluR1 and GluR2/3) and spinothalamic tract cells.
    Neuroreport, 1996
    Co-Authors: Zaiming Ye, Karin N. Westlund
    Abstract:

    THE associations of Glutamate Receptor subunits (NMDARI, AMPA GluR1 and GluR2/3) and spinothalamic tract neurons in the rat lumbar spinal cord dorsal horn were investigated. Staining for NMDARI and AMPA GluR1 and GluR2/3 Receptor subunits was observed throughout the spinothalamic tract soma and dendrites, particularly in association with the rough endoplasmic reticulum and some postsynaptic membrane sites. Immunostaining for NMDARI and AMPA GluR2/3 was also noted in presynaptic membrane sites. Localization of both NMDA and AMPA Glutamate Receptor subunits in association with spinothalamic tract neurons provides anatomical evidence in support of the various interactions reported for Glutamate Receptors in nociception. Presynaptic localization of the AMPA GluR2/3 Receptor subunit suggests that spinothalamic tract cells may also be affected presynaptically by AMPA Glutamate Receptor interactions.

  • Ultrastructural localization of Glutamate Receptor subunits (NMDAR1, AMPA GluR1 and GluR2/3) and spinothalamic tract cells.
    Neuroreport, 1996
    Co-Authors: Zaiming Ye, Karin N. Westlund
    Abstract:

    The associations of Glutamate Receptor subunits (NMDAR1, AMPA GluR1 and GluR2/3) and spinothalamic tract neurons in the rat lumbar spinal cord dorsal horn were investigated. Staining for NMDAR1 and AMPA GluR1 and GluR2/3 Receptor subunits was observed throughout the spinothalamic tract soma and dendrites, particularly in association with the rough endoplasmic reticulum and some postsynaptic membrane sites. Immunostaining for NMDAR1 and AMPA GluR2/3 was also noted in presynaptic membrane sites. Localization of both NMDA and AMPA Glutamate Receptor subunits in association with spinothalamic tract neurons provides anatomical evidence in support of the various interactions reported for Glutamate Receptors in nociception. Presynaptic localization of the AMPA GluR2/3 Receptor subunit suggests that spinothalamic tract cells may also be affected presynaptically by AMPA Glutamate Receptor interactions.