Glutamate Receptor Ion Channels: Structure, Regulation, and Function
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A Guide to Glutamate Receptors
A guide to glutamate receptors 1 Contents Glutamate receptors . 4 Ionotropic glutamate receptors . 4 - Structure ........................................................................................................... 4 - Function ............................................................................................................ 5 - AMPA receptors ................................................................................................. 6 - NMDA receptors ................................................................................................. 6 - Kainate receptors ............................................................................................... 6 Metabotropic glutamate receptors . 8 - Structure ........................................................................................................... 8 - Function ............................................................................................................ 9 - Group I: mGlu1 and mGlu5. .9 - Group II: mGlu2 and mGlu3 ................................................................................. 10 - Group III: mGlu4, mGlu6, mGlu7 and mGlu8 ............................................................ 10 Protocols and webinars . 11 - Protocols ......................................................................................................... 11 - Webinars ......................................................................................................... 12 References and further reading . 13 Excitatory synapse pathway -
Amnestic Concentrations of Sevoflurane Inhibit Synaptic
Anesthesiology 2008; 108:447–56 Copyright © 2008, the American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins, Inc. Amnestic Concentrations of Sevoflurane Inhibit Synaptic Plasticity of Hippocampal CA1 Neurons through ␥-Aminobutyric Acid–mediated Mechanisms Junko Ishizeki, M.D.,* Koichi Nishikawa, M.D., Ph.D.,† Kazuhiro Kubo, M.D.,‡ Shigeru Saito, M.D., Ph.D.,§ Fumio Goto, M.D., Ph.D. Background: The cellular mechanisms of anesthetic-induced for surgical procedures do not have recollection of ac- amnesia are still poorly understood. The current study exam- tually being awake despite being awake and cooperative ined sevoflurane at various concentrations in the CA1 region of during the procedure.1 Galinkin et al.2 compared sub- rat hippocampal slices for effects on excitatory synaptic trans- Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/108/3/447/366512/0000542-200803000-00017.pdf by guest on 29 September 2021 mission and on long-term potentiation (LTP), as a possible jective, psychomotor, cognitive, and analgesic effects of mechanism contributing to anesthetic-induced loss of recall. sevoflurane (0.3% and 0.6%) with those of nitrous oxide Methods: Population spikes and field excitatory postsynaptic at equal minimum alveolar concentrations (MACs) in potentials were recorded using extracellular electrodes after healthy volunteers. They found that sevoflurane pro- electrical stimulation of Schaffer-collateral-commissural fiber inputs. Paired pulse facilitation was used as a measure of pre- duced a greater degree of amnesia and psychomotor synaptic effects of the anesthetic. LTP was induced using tetanic impairment than did an equal MAC of nitrous oxide but stimulation (100 Hz, 1 s). Sevoflurane at concentrations from had no analgesic actions. -
Effects of Chronic Systemic Low-Impact Ampakine Treatment On
Biomedicine & Pharmacotherapy 105 (2018) 540–544 Contents lists available at ScienceDirect Biomedicine & Pharmacotherapy journal homepage: www.elsevier.com/locate/biopha Effects of chronic systemic low-impact ampakine treatment on neurotrophin T expression in rat brain ⁎ Daniel P. Radin , Steven Johnson, Richard Purcell, Arnold S. Lippa RespireRx Pharmaceuticals, Inc., 126 Valley Road, Glen Rock, NJ, 07452, United States ARTICLE INFO ABSTRACT Keywords: Neurotrophin dysregulation has been implicated in a large number of neurodegenerative and neuropsychiatric Ampakine diseases. Unfortunately, neurotrophins cannot cross the blood brain barrier thus, novel means of up regulating BDNF their expression are greatly needed. It has been demonstrated previously that neurotrophins are up regulated in Cognitive enhancement response to increases in brain activity. Therefore, molecules that act as cognitive enhancers may provide a LTP clinical means of up regulating neurotrophin expression. Ampakines are a class of molecules that act as positive Neurotrophin allosteric modulators of AMPA-type glutamate receptors. Currently, they are being developed to prevent opioid- NGF induced respiratory depression without sacrificing the analgesic properties of the opioids. In addition, these molecules increase neuronal activity and have been shown to restore age-related deficits in LTP in aged rats. In the current study, we examined whether two different ampakines could increase levels of BDNF and NGF at doses that are active in behavioral measures of cognition. Results demonstrate that ampakines CX516 and CX691 induce differential increases in neurotrophins across several brain regions. Notable increases in NGF were ob- served in the dentate gyrus and piriform cortex while notable BDNF increases were observed in basolateral and lateral nuclei of the amygdala. -
Glycine Activated Ion Channel Subunits Encoded by Ctenophore
Glycine activated ion channel subunits encoded by PNAS PLUS ctenophore glutamate receptor genes Robert Albersteina, Richard Greya, Austin Zimmeta, David K. Simmonsb, and Mark L. Mayera,1 aLaboratory of Cellular and Molecular Neurophysiology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892; and bThe Whitney Laboratory for Marine Bioscience, University of Florida, St. Augustine, FL 32080 Edited by Christopher Miller, Howard Hughes Medical Institute, Brandeis University, Waltham, MA, and approved September 2, 2015 (received for review July 13, 2015) Recent genome projects for ctenophores have revealed the subunits and glutamate to GluN2 subunits for activation of ion presence of numerous ionotropic glutamate receptors (iGluRs) in channel gating (12, 14–17), as well as depolarization to relieve + Mnemiopsis leidyi and Pleurobrachia bachei, among our earliest ion channel block by extracellular Mg2 (18, 19). The initial metazoan ancestors. Sequence alignments and phylogenetic analy- annotation of the M. leidyi genome identified 16 candidate iGluR sis show that these form a distinct clade from the well-characterized genes (4), whereas in the draft genome of P. bachei, 14 iGluRs AMPA, kainate, and NMDA iGluR subtypes found in vertebrates. were annotated as kainate-like receptors (5). In view of growing Although annotated as glutamate and kainate receptors, crystal interest in the molecular evolution of ion channels and receptors, structures of the ML032222a and PbiGluR3 ligand-binding domains and the pivotal role that ctenophores play in our current un- (LBDs) reveal endogenous glycine in the binding pocket, whereas derstanding of nervous system development (20), we initiated a ligand-binding assays show that glycine binds with nanomolar af- structural and functional characterization of glutamate receptors finity; biochemical assays and structural analysis establish that glu- expressed in both species. -
Picrotoxin-Like Channel Blockers of GABAA Receptors
COMMENTARY Picrotoxin-like channel blockers of GABAA receptors Richard W. Olsen* Department of Molecular and Medical Pharmacology, Geffen School of Medicine, University of California, Los Angeles, CA 90095-1735 icrotoxin (PTX) is the prototypic vous system. Instead of an acetylcholine antagonist of GABAA receptors (ACh) target, the cage convulsants are (GABARs), the primary media- noncompetitive GABAR antagonists act- tors of inhibitory neurotransmis- ing at the PTX site: they inhibit GABAR Psion (rapid and tonic) in the nervous currents and synapses in mammalian neu- system. Picrotoxinin (Fig. 1A), the active rons and inhibit [3H]dihydropicrotoxinin ingredient in this plant convulsant, struc- binding to GABAR sites in brain mem- turally does not resemble GABA, a sim- branes (7, 9). A potent example, t-butyl ple, small amino acid, but it is a polycylic bicyclophosphorothionate, is a major re- compound with no nitrogen atom. The search tool used to assay GABARs by compound somehow prevents ion flow radio-ligand binding (10). through the chloride channel activated by This drug target appears to be the site GABA in the GABAR, a member of the of action of the experimental convulsant cys-loop, ligand-gated ion channel super- pentylenetetrazol (1, 4) and numerous family. Unlike the competitive GABAR polychlorinated hydrocarbon insecticides, antagonist bicuculline, PTX is clearly a including dieldrin, lindane, and fipronil, noncompetitive antagonist (NCA), acting compounds that have been applied in not at the GABA recognition site but per- huge amounts to the environment with haps within the ion channel. Thus PTX major agricultural economic impact (2). ͞ appears to be an excellent example of al- Some of the other potent toxicants insec- losteric modulation, which is extremely ticides were also radiolabeled and used to important in protein function in general characterize receptor action, allowing and especially for GABAR (1). -
Characterization of a Domoic Acid Binding Site from Pacific Razor Clam
Aquatic Toxicology 69 (2004) 125–132 Characterization of a domoic acid binding site from Pacific razor clam Vera L. Trainer∗, Brian D. Bill NOAA Fisheries, Northwest Fisheries Science Center, Marine Biotoxin Program, 2725 Montlake Blvd. E., Seattle, WA 98112, USA Received 5 November 2003; received in revised form 27 April 2004; accepted 27 April 2004 Abstract The Pacific razor clam, Siliqua patula, is known to retain domoic acid, a water-soluble glutamate receptor agonist produced by diatoms of the genus Pseudo-nitzschia. The mechanism by which razor clams tolerate high levels of the toxin, domoic acid, in their tissues while still retaining normal nerve function is unknown. In our study, a domoic acid binding site was solubilized from razor clam siphon using a combination of Triton X-100 and digitonin. In a Scatchard analysis using [3H]kainic acid, the partially-purified membrane showed two distinct receptor sites, a high affinity, low capacity site with a KD (mean ± S.E.) of 28 ± 9.4 nM and a maximal binding capacity of 12 ± 3.8 pmol/mg protein and a low affinity, high capacity site with a mM affinity for radiolabeled kainic acid, the latter site which was lost upon solubilization. Competition experiments showed that the rank order potency for competitive ligands in displacing [3H]kainate binding from the membrane-bound receptors was quisqualate > ibotenate > iodowillardiine = AMPA = fluorowillardiine > domoate > kainate > l-glutamate. At high micromolar concentrations, NBQX, NMDA and ATPA showed little or no ability to displace [3H]kainate. In contrast, Scatchard analysis 3 using [ H]glutamate showed linearity, indicating the presence of a single binding site with a KD and Bmax of 500 ± 50 nM and 14 ± 0.8 pmol/mg protein, respectively. -
Pharmacological Modulation of Processes Contributing to Spinal Hyperexcitability: Electrophysiological Studies in the Rat
Pharmacological modulation of processes contributing to spinal hyperexcitability: electrophysiological studies in the rat. By Katherine J Carpenter A thesis submitted to the University of London for the degree of Doctor of Philosophy Department of Pharmacology University College London Gower Street London WC1E6BT ProQuest Number: U642184 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. uest. ProQuest U642184 Published by ProQuest LLC(2015). Copyright of the Dissertation is held by the Author. All rights reserved. This work is protected against unauthorized copying under Title 17, United States Code. Microform Edition © ProQuest LLC. ProQuest LLC 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106-1346 Abstract Two of the most effective analgesic strategies in man are (i) blockade of the NMDA receptor for glutamate, which plays a major role in nociceptive transmission and (ii) augmentation of inhibitory systems, exemplified by the use of ketamine and the opioids respectively. Both are, however, are associated with side effects. Potential novel analgesic targets are investigated here using in vivo electrophysiology in the anaesthetised rat with pharmacological manipulation of spinal neuronal transmission. Three different approaches were used to target NMDA receptors: (i) glycine site antagonists (Mrz 2/571 and Mrz 2/579), (ii) antagonists selective for receptors containing the NR2B subunit (ifenprodil and ACEA-1244), (iii) elevating the levels of N-acetyl-aspartyl- glutamate (NAAG), an endogenous peptide, by inhibition of its degradative enzyme. -
Advances in the Synthesis of 5- and 6-Substituted Uracil Derivatives
701xml UOPP_A_438055 October 9, 2009 12:27 UOPP #438055, VOL 41, ISS 6 Advances in the Synthesis of 5- and 6-Substituted Uracil Derivatives Javier I. Bardag´ı and Roberto A. Rossi QUERY SHEET This page lists questions we have about your paper. The numbers displayed at left can be found in the text of the paper for reference. In addition, please review your paper as a whole for correctness. There are no Editor Queries for this paper. TABLE OF CONTENTS LISTING The table of contents for the journal will list your paper exactly as it appears below: Advances in the Synthesis of 5- and 6-Substituted Uracil Derivatives Javier I. Bardag´ı and Roberto A. Rossi 701xml UOPP_A_438055 October 9, 2009 12:27 Organic Preparations and Procedures International, 41:1–36, 2009 Copyright © Taylor & Francis Group, LLC ISSN: 0030-4948 print DOI: 10.1080/00304940903378776 Advances in the Synthesis of 5- and 6-Substituted Uracil Derivatives Javier I. Bardag´ı and Roberto A. Rossi INFIQC, Departamento de Qu´ımica Organica,´ Facultad de Ciencias Qu´ımicas, Universidad Nacional de Cordoba,´ Ciudad Universitaria, 5000 Cordoba,´ ARGENTINA INTRODUCTION ................................................................................... 2 I. Uracils with Carbon-based Substituent ................................................. 3 1. C(Uracil)-C(sp3) Bonds............................................................................ 3 a. Perfluoroalkyl Compounds...................................................................12 2. C(Uracil)-C(sp2) Bonds...........................................................................13 -
(19) United States (12) Patent Application Publication (10) Pub
US 20130289061A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2013/0289061 A1 Bhide et al. (43) Pub. Date: Oct. 31, 2013 (54) METHODS AND COMPOSITIONS TO Publication Classi?cation PREVENT ADDICTION (51) Int. Cl. (71) Applicant: The General Hospital Corporation, A61K 31/485 (2006-01) Boston’ MA (Us) A61K 31/4458 (2006.01) (52) U.S. Cl. (72) Inventors: Pradeep G. Bhide; Peabody, MA (US); CPC """"" " A61K31/485 (201301); ‘4161223011? Jmm‘“ Zhu’ Ansm’ MA. (Us); USPC ......... .. 514/282; 514/317; 514/654; 514/618; Thomas J. Spencer; Carhsle; MA (US); 514/279 Joseph Biederman; Brookline; MA (Us) (57) ABSTRACT Disclosed herein is a method of reducing or preventing the development of aversion to a CNS stimulant in a subject (21) App1_ NO_; 13/924,815 comprising; administering a therapeutic amount of the neu rological stimulant and administering an antagonist of the kappa opioid receptor; to thereby reduce or prevent the devel - . opment of aversion to the CNS stimulant in the subject. Also (22) Flled' Jun‘ 24’ 2013 disclosed is a method of reducing or preventing the develop ment of addiction to a CNS stimulant in a subj ect; comprising; _ _ administering the CNS stimulant and administering a mu Related U‘s‘ Apphcatlon Data opioid receptor antagonist to thereby reduce or prevent the (63) Continuation of application NO 13/389,959, ?led on development of addiction to the CNS stimulant in the subject. Apt 27’ 2012’ ?led as application NO_ PCT/US2010/ Also disclosed are pharmaceutical compositions comprising 045486 on Aug' 13 2010' a central nervous system stimulant and an opioid receptor ’ antagonist. -
Regulation of Extracellular Arginine Levels in the Hippocampus in Vivo
Regulation of Extracellular Arginine Levels in the Hippocampus In Vivo by Joanne Watts B.Sc. (Hons) r Thesis submitted for the degree of Doctor of Philosophy in the Faculty of Science, University of London The School of Pharmacy University of London ProQuest Number: 10105113 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. uest. ProQuest 10105113 Published by ProQuest LLC(2016). Copyright of the Dissertation is held by the Author. All rights reserved. This work is protected against unauthorized copying under Title 17, United States Code. Microform Edition © ProQuest LLC. ProQuest LLC 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106-1346 Abstract Nitric oxide (NO) has emerged as an ubiquitous signaling molecule in the central nervous system (CNS). NO is synthesised from molecular oxygen and the amino acid L-arginine (L- ARG) by the enzyme NO synthase (NOS), and the availability of L-ARG has been implicated as the limiting factor for NOS activity. Previous studies have indicated that L- ARG is localised in astrocytes in vitro and that the in vitro activation of non-N-methyl-D- aspartate (NMDA) receptors, as well as the presence of peroxynitrite (ONOO ), led to the release of L-ARG. Microdialysis was therefore used in this study to investigate whether this held true in vivo. -
NINDS Custom Collection II
ACACETIN ACEBUTOLOL HYDROCHLORIDE ACECLIDINE HYDROCHLORIDE ACEMETACIN ACETAMINOPHEN ACETAMINOSALOL ACETANILIDE ACETARSOL ACETAZOLAMIDE ACETOHYDROXAMIC ACID ACETRIAZOIC ACID ACETYL TYROSINE ETHYL ESTER ACETYLCARNITINE ACETYLCHOLINE ACETYLCYSTEINE ACETYLGLUCOSAMINE ACETYLGLUTAMIC ACID ACETYL-L-LEUCINE ACETYLPHENYLALANINE ACETYLSEROTONIN ACETYLTRYPTOPHAN ACEXAMIC ACID ACIVICIN ACLACINOMYCIN A1 ACONITINE ACRIFLAVINIUM HYDROCHLORIDE ACRISORCIN ACTINONIN ACYCLOVIR ADENOSINE PHOSPHATE ADENOSINE ADRENALINE BITARTRATE AESCULIN AJMALINE AKLAVINE HYDROCHLORIDE ALANYL-dl-LEUCINE ALANYL-dl-PHENYLALANINE ALAPROCLATE ALBENDAZOLE ALBUTEROL ALEXIDINE HYDROCHLORIDE ALLANTOIN ALLOPURINOL ALMOTRIPTAN ALOIN ALPRENOLOL ALTRETAMINE ALVERINE CITRATE AMANTADINE HYDROCHLORIDE AMBROXOL HYDROCHLORIDE AMCINONIDE AMIKACIN SULFATE AMILORIDE HYDROCHLORIDE 3-AMINOBENZAMIDE gamma-AMINOBUTYRIC ACID AMINOCAPROIC ACID N- (2-AMINOETHYL)-4-CHLOROBENZAMIDE (RO-16-6491) AMINOGLUTETHIMIDE AMINOHIPPURIC ACID AMINOHYDROXYBUTYRIC ACID AMINOLEVULINIC ACID HYDROCHLORIDE AMINOPHENAZONE 3-AMINOPROPANESULPHONIC ACID AMINOPYRIDINE 9-AMINO-1,2,3,4-TETRAHYDROACRIDINE HYDROCHLORIDE AMINOTHIAZOLE AMIODARONE HYDROCHLORIDE AMIPRILOSE AMITRIPTYLINE HYDROCHLORIDE AMLODIPINE BESYLATE AMODIAQUINE DIHYDROCHLORIDE AMOXEPINE AMOXICILLIN AMPICILLIN SODIUM AMPROLIUM AMRINONE AMYGDALIN ANABASAMINE HYDROCHLORIDE ANABASINE HYDROCHLORIDE ANCITABINE HYDROCHLORIDE ANDROSTERONE SODIUM SULFATE ANIRACETAM ANISINDIONE ANISODAMINE ANISOMYCIN ANTAZOLINE PHOSPHATE ANTHRALIN ANTIMYCIN A (A1 shown) ANTIPYRINE APHYLLIC -
Aniracetam Reduces Glutamate Receptor Desensitization and Slows
Proc. Natl. Acad. Sci. USA Vol. 88, pp. 10936-10940, December 1991 Neurobiology Aniracetam reduces glutamate receptor desensitization and slows the decay of fast excitatory synaptic currents in the hippocampus (non-N-methyl-D-aspartate receptor/synapse) JEFFRY S. ISAACSON*t AND ROGER A. NICOLLtt *Physiology Graduate Program and the Departments of SPharmacology and tPhysiology, University of California, San Francisco, CA 94143-0450 Communicated by Floyd E. Bloom, September 16, 1991 ABSTRACT Aniracetam is a nootropic drug that has been and DL-2-amino-5-phosphonovaleric acid (50 ,uM) were shown to selectively enhance quisqualate receptor-mediated added to the medium to block y-aminobutyric acid type A responses inXenopus oocytes injected with brain mRNA and in (GABAA) receptors and NMDA receptors, respectively. In hippocampal pyramidal cells [Ito, I., Tanabe, S., Kohda, A. & the majority of experiments examining iontophoretic re- Sugiyama, H. (1990) J. Physiol. (London) 424, 533-544]. We sponses, tetrodotoxin (0.5-1 1uM) was included to block have used patch clamp recording techniques in hippocampal sodium-dependent action potentials. Currents were recorded slices to elucidate the mechanism for this selective action. We with an Axopatch 1B amplifier from neurons in the CA1 and find that aniracetam enhances glutamate-evoked currents in CA3 pyramidal cell layers and granule cell layer of the whole-cell recordings and, in outside-out patches, strongly dentate gyrus using the "blind" whole-cell recording tech- reduces glutamate receptor desensitization. In addition, nique (15, 16). Patch electrodes (tip diameter = 2 Ium) aniracetam selectively prolongs the time course and increases contained (in mM) either a CsF (110 CsF, 10 CsCl, 10 Hepes, the peak amplitude of fast synaptic currents.