DOCSLIB.ORG

Kainate Receptors and Synaptic Transmission James E

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Kainate Receptors and Synaptic Transmission James E Progress in Neurobiology 70 (2003) 387–407 Kainate receptors and synaptic transmission James E. Huettner∗ Department of Cell Biology and Physiology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA Received 20 February 2003; accepted 25 July 2003 Abstract Excitatory glutamatergic transmission involves a variety of different receptor types, each with distinct properties and functions. Physiolog- ical studies have identified both post- and presynaptic roles for kainate receptors, which are a subtype of the ionotropic glutamate receptors. Kainate receptors contribute to excitatory postsynaptic currents in many regions of the central nervous system including hippocampus, cortex, spinal cord and retina. In some cases, postsynaptic kainate receptors are co-distributed with ␣-amino-3-hydroxy-5-methyl-4- isoxazolepropionic acid (AMPA) and N-methyl-d-aspartate (NMDA) receptors, but there are also synapses where transmission is mediated exclusively by postsynaptic kainate receptors: for example, in the retina at connections made by cones onto off bipolar cells. Modulation of transmitter release by presynaptic kainate receptors can occur at both excitatory and inhibitory synapses. The depolarization of nerve terminals by current flow through ionotropic kainate receptors appears sufficient to account for most examples of presynaptic regulation; however, a number of studies have provided evidence for metabotropic effects on transmitter release that can be initiated by activation of kainate receptors. Recent analysis of knockout mice lacking one or more of the subunits that contribute to kainate receptors, as well as studies with subunit-selective agonists and antagonists, have revealed the important roles that kainate receptors play in short- and long-term synaptic plasticity. This review briefly addresses the properties of kainate receptors and considers in greater detail the physiological analysis of their contributions to synaptic transmission. © 2003 Elsevier Ltd. All rights reserved. Contents 1. Introduction .......................................................................... 388 2. Kainate receptor properties ............................................................ 388 3. Kainate receptor distribution and function ............................................... 390 3.1. Hippocampus .................................................................. 390 3.1.1. Presynaptic receptors ................................................... 390 3.1.2. Postsynaptic receptors .................................................. 395 3.1.3. Transgenic mice ....................................................... 396 3.1.4. Synaptic plasticity...................................................... 398 3.2. Cortex ......................................................................... 398 3.3. Amygdala...................................................................... 399 3.4. Retina ......................................................................... 399 3.5. Striatum ....................................................................... 400 3.6. Hypothalamus .................................................................. 400 Abbreviations: GYKI53655, 1-(4-aminophenyl)-3-methylcarbamyl-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiazepine; SYM2081, 2S, 4R-4-methylglutamate; SYM2206, (±)-4-(4-aminophenyl)-1,2-dihydro-1-methyl-2-propylcarbamoyl-6,7-methylenedioxyphthalazine; CNQX, 6-cyano- 7-nitroquinoxaline-2,3-dione; APV, 2-amino-5-phosphono-valerate; NMDA, N-methyl-d-aspartate; CPCCOEt, 7-(hydroxyimino)cyclopropa[β]-chromen- 1␣-carboxylate ethylester; AMPA, ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; ATPA, (RS)-2-amino-3-(3-hydroxy-5-tertbutylisoxazol-4- yl)propanoic acid; DRG, dorsal root ganglion; trans-PDC, trans-pyrrolidine-2,4-carboxylic acid; TTX, tetrodotoxin ∗ Tel.: +1-314-362-6624; fax: +1-314-362-7463. E-mail address: [email protected] (J.E. Huettner). URL: http://www.cellbio.wustl.edu/faculty/huettner/. 0301-0082/$ – see front matter © 2003 Elsevier Ltd. All rights reserved. doi:10.1016/S0301-0082(03)00122-9 388 J.E. Huettner / Progress in Neurobiology 70 (2003) 387–407 3.7. Cerebellum ...................................................................... 400 3.8. Spinal cord ...................................................................... 401 3.9. Dorsal root ganglia ............................................................... 401 4. Perspectives ............................................................................ 402 Acknowledgements .......................................................................... 402 References .................................................................................. 402 1. Introduction rents (Kiskin et al., 1986; Keinänen et al., 1990; Patneau and Mayer, 1991), and AMPA can activate at least some types Kainate receptors are one of three subtypes of ionotropic of kainate receptor (Herb et al., 1992). receptors for the excitatory transmitter l-glutamate There are five different subunits that contribute to kainate (Dingledine et al., 1999). The other two subtypes, which receptors (Hollmann and Heinemann, 1994). They fall into are named for the synthetic agonists N-methyl-d-aspartate two families, based on sequence homology and agonist bind- 2 (NMDA) and ␣-amino-3-hydroxy-5-methyl-4-isoxazolepro- ing properties. GLUK5, GLUK6 and GLUK7 are approxi- pionic acid (AMPA), are known to mediate postsynaptic mately 70% identical (Bettler et al., 1990, 1992; Egebjerg currents at excitatory synapses throughout the brain and et al., 1991; Sommer et al., 1992). The GLUK1 and GLUK2 spinal cord (Mayer and Westbrook, 1987). The physiologi- subunits also are 70% identical (Werner et al., 1991; Herb cal properties of kainate receptors (Chittajallu et al., 1999; et al., 1992; Sakimura et al., 1992), but share only 40% Lerma et al., 2001), and their roles in synaptic transmission identity with GLUK5, GLUK6 and GLUK7. Both families (Frerking and Nicoll, 2000; Kullmann, 2001; Lerma, 2003), of kainate receptor subunits also display weaker identity have been discerned only recently, following the discovery with subunits of AMPA (30–35%) and NMDA receptors of selective antagonists that allow for isolation of kainate (10–20%). In addition, all of the glutamate receptor sub- receptor-mediated currents (Paternain et al., 1995; Wilding units are thought to adopt the same membrane topology. The and Huettner, 1995; Bleakman et al., 1996a). Additional amino terminal half of each subunit is extracellular. There interest in kainate receptors has been raised by the cloning are four hydrophobic segments: three membrane spanning and characterization of their subunit cDNAs (Hollmann domains and a “p-loop” that dips into the membrane from and Heinemann, 1994), and by the recognition that kainate the cytoplasmic face to form the pore (Hollmann et al., 1994; receptor subunits are distinct from subunits that contribute Roche et al., 1994; Bennett and Dingledine, 1995). to AMPA receptors (Boulter et al., 1990; Keinänen et al., The GLUK5 and GLUK6 subunits, but not the other 1990) and to NMDA receptors (Kutsuwada et al., 1992; kainate receptor subunits, can undergo mRNA editing that Monyer et al., 1992; Moriyoshi et al., 1991). changes an amino acid in the channel pore and regulates per- meation properties (Sommer et al., 1991). For both GLUK5 and GLUK6, as well as the GLUA2 subunit of AMPA recep- 2. Kainate receptor properties tors, the genomic sequence encodes a glutamine residue in the edited location in the p-loop that is converted by editing Kainate receptors were originally defined by Watkins and to code for an arginine (Sommer et al., 1991). In all three coworkers (Davies et al., 1979; Watkins and Evans, 1981) cases, mature receptors comprised of unedited subunits dis- based on the pharmacology of neuronal responses to excita- play inwardly rectifying current–voltage (I–V) relations ow- tory amino acids. In particular, the selective depolarization ing to block of outward current by intracellular polyamines, of isolated dorsal root fibers by kainate led them to propose whereas receptors including edited subunits resist polyamine a unique receptor for kainate that was distinct from the bind- block and have linear I–V relations (Bowie and Mayer, ing sites activated by NMDA and AMPA.1 Subsequent work 1995; Kamboj et al., 1995; Isa et al., 1995; Donevan and has confirmed the existence of three different receptor sub- Rogawski, 1995; Koh et al., 1995; Bähring et al., 1997). types (Hollmann and Heinemann, 1994; Dingledine et al., Editing at the Q/R site also determines single channel 1999), although it also has been recognized that many ex- conductance and calcium permeability. Fully unedited citatory amino acids, including kainate and AMPA, are not receptors exhibit a higher relative calcium permeability entirely selective for only one receptor class. Thus, kainate (Egebjerg and Heinemann, 1993; Burnashev et al., 1995, activates AMPA receptors to produce large sustained cur- 1996) and a higher unitary conductance (Howe, 1996; Swanson et al., 1996) as compared to receptors that include one or more edited subunits. In addition to the Q/R site, the 1 The original classification proposed by Watkins and coworkers iden- tified NMDA, kainate and quisqualate receptors; however, AMPA was subsequently recognized as a more selective agonist than quisqualate and 2 IUPHAR nomenclature (Lodge and Dingledine, 2000) used throughout the classification was
Load more

Recommended publications
  • 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
    [Show full text]
  • Determining the Role of Gabaergic Signaling in The
    DETERMINING THE ROLE OF GABAERGIC SIGNALING IN THE CRANIOFACIAL DEVELOPMENT OF LARVAL ZEBRAFISH by LINDSEY L. BEEBE (Under the Direction of James D. Lauderdale) ABSTRACT Although best known as an inhibitory neurotransmitter, intriguing evidence has implicated GABA as a key signaling molecule in craniofacial development in mammals. Glutamate is converted to GABA by an enzyme called glutamic acid decarboxylase (GAD), which exists in two isoforms, GAD67 and GAD65. The GAD1 and GAD2 genes encode these isoforms, respectively. A decrease in GAD activity in the human brain is often associated with epilepsy, schizophrenia and related neurological disorders. In mice and humans, mutations in gad1, but not gad2, result in defects in palate development, and mutations in the Gabrb3 gene, which encodes the β3 subunit of the GABAA receptor, exhibit a comparable phenotype to gad1 mutations. These results suggest that GABA signaling, through the GABAA receptor, can play an important and conserved role in craniofacial development. However, the mechanism of this process is not known and cannot be easily investigated in a mammalian system. In this work, translation-blocking morpholinos against the GAD genes were used to alter expression within the larval zebrafish. While gad2 morphants looked phenotypically normal, gad1 morphant animals exhibited altered cranial structures at 1 and 7 dpf. Yet, both gad1 and gad2 morphants exhibited spontaneous seizure-like neural activity. Through the use of photoactivatable caged-morpholinos, the craniofacial deformities could be bypassed when photolysis was carried out at 24 hpf. Electrophysiological recordings showed that while dark-raised CyHQ-gad1 morphant animals looked phenotypically comparable to wild-type animals, they exhibited abnormal, seizure-like neural activity.
    [Show full text]
  • 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.
    [Show full text]
  • Neurotransmitters-Drugs Andbrain Function.Pdf
    Neurotransmitters, Drugs and Brain Function. Edited by Roy Webster Copyright & 2001 John Wiley & Sons Ltd ISBN: Hardback 0-471-97819-1 Paperback 0-471-98586-4 Electronic 0-470-84657-7 Neurotransmitters, Drugs and Brain Function Neurotransmitters, Drugs and Brain Function. Edited by Roy Webster Copyright & 2001 John Wiley & Sons Ltd ISBN: Hardback 0-471-97819-1 Paperback 0-471-98586-4 Electronic 0-470-84657-7 Neurotransmitters, Drugs and Brain Function Edited by R. A. Webster Department of Pharmacology, University College London, UK JOHN WILEY & SONS, LTD Chichester Á New York Á Weinheim Á Brisbane Á Singapore Á Toronto Neurotransmitters, Drugs and Brain Function. Edited by Roy Webster Copyright & 2001 John Wiley & Sons Ltd ISBN: Hardback 0-471-97819-1 Paperback 0-471-98586-4 Electronic 0-470-84657-7 Copyright # 2001 by John Wiley & Sons Ltd. Bans Lane, Chichester, West Sussex PO19 1UD, UK National 01243 779777 International ++44) 1243 779777 e-mail +for orders and customer service enquiries): [email protected] Visit our Home Page on: http://www.wiley.co.uk or http://www.wiley.com All Rights Reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording, scanning or otherwise, except under the terms of the Copyright, Designs and Patents Act 1988 or under the terms of a licence issued by the Copyright Licensing Agency Ltd, 90 Tottenham Court Road, London W1P0LP,UK, without the permission in writing of the publisher. Other Wiley Editorial Oces John Wiley & Sons, Inc., 605 Third Avenue, New York, NY 10158-0012, USA WILEY-VCH Verlag GmbH, Pappelallee 3, D-69469 Weinheim, Germany John Wiley & Sons Australia, Ltd.
    [Show full text]
  • GABA Receptors
    D Reviews • BIOTREND Reviews • BIOTREND Reviews • BIOTREND Reviews • BIOTREND Reviews Review No.7 / 1-2011 GABA receptors Wolfgang Froestl , CNS & Chemistry Expert, AC Immune SA, PSE Building B - EPFL, CH-1015 Lausanne, Phone: +41 21 693 91 43, FAX: +41 21 693 91 20, E-mail: [email protected] GABA Activation of the GABA A receptor leads to an influx of chloride GABA ( -aminobutyric acid; Figure 1) is the most important and ions and to a hyperpolarization of the membrane. 16 subunits with γ most abundant inhibitory neurotransmitter in the mammalian molecular weights between 50 and 65 kD have been identified brain 1,2 , where it was first discovered in 1950 3-5 . It is a small achiral so far, 6 subunits, 3 subunits, 3 subunits, and the , , α β γ δ ε θ molecule with molecular weight of 103 g/mol and high water solu - and subunits 8,9 . π bility. At 25°C one gram of water can dissolve 1.3 grams of GABA. 2 Such a hydrophilic molecule (log P = -2.13, PSA = 63.3 Å ) cannot In the meantime all GABA A receptor binding sites have been eluci - cross the blood brain barrier. It is produced in the brain by decarb- dated in great detail. The GABA site is located at the interface oxylation of L-glutamic acid by the enzyme glutamic acid decarb- between and subunits. Benzodiazepines interact with subunit α β oxylase (GAD, EC 4.1.1.15). It is a neutral amino acid with pK = combinations ( ) ( ) , which is the most abundant combi - 1 α1 2 β2 2 γ2 4.23 and pK = 10.43.
    [Show full text]
  • Interplay Between Gating and Block of Ligand-Gated Ion Channels
    brain sciences Review Interplay between Gating and Block of Ligand-Gated Ion Channels Matthew B. Phillips 1,2, Aparna Nigam 1 and Jon W. Johnson 1,2,* 1 Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA 15260, USA; [email protected] (M.B.P.); [email protected] (A.N.) 2 Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA 15260, USA * Correspondence: [email protected]; Tel.: +1-(412)-624-4295 Received: 27 October 2020; Accepted: 26 November 2020; Published: 1 December 2020 Abstract: Drugs that inhibit ion channel function by binding in the channel and preventing current flow, known as channel blockers, can be used as powerful tools for analysis of channel properties. Channel blockers are used to probe both the sophisticated structure and basic biophysical properties of ion channels. Gating, the mechanism that controls the opening and closing of ion channels, can be profoundly influenced by channel blocking drugs. Channel block and gating are reciprocally connected; gating controls access of channel blockers to their binding sites, and channel-blocking drugs can have profound and diverse effects on the rates of gating transitions and on the stability of channel open and closed states. This review synthesizes knowledge of the inherent intertwining of block and gating of excitatory ligand-gated ion channels, with a focus on the utility of channel blockers as analytic probes of ionotropic glutamate receptor channel function. Keywords: ligand-gated ion channel; channel block; channel gating; nicotinic acetylcholine receptor; ionotropic glutamate receptor; AMPA receptor; kainate receptor; NMDA receptor 1. Introduction Neuronal information processing depends on the distribution and properties of the ion channels found in neuronal membranes.
    [Show full text]
  • Cell Surface Mobility of GABAB Receptors Saad Bin
    Cell surface mobility of GABAB receptors Saad Bin Hannan September 2011 A thesis submitted in fulfilment of the requirements for the degree of Doctor of Philosophy of the University College London Department of Neuroscience, Physiology, and Pharmacology University College London Gower Street London WC1E 6BT UK Declaration ii ‘I, Saad Hannan confirm that the work presented in this thesis is my own. Where information has been derived from other sources, I confirm that this has been indicated in the thesis.' ____________________ Saad Hannan September 2011 To Ammu, Abbu, Polu Abstract ivi Abstract Type-B γ-aminobutyric acid receptors (GABABRs) are important for mediating slow inhibition in the central nervous system and the kinetics of their internalisation and lateral mobility will be a major determinant of their signalling efficacy. Functional GABABRs require R1 and R2 subunit co-assembly, but how heterodimerisation affects the trafficking kinetics of GABABRs is unknown. Here, an α- bungarotoxin binding site (BBS) was inserted into the N-terminus of R2 to monitor receptor mobility in live cells. GABABRs are internalised via clathrin- and dynamin- dependent pathways and recruited to endosomes. By mutating the BBS, a new technique was developed to differentially track R1a and R2 simultaneously, revealing the subunits internalise as heteromers and that R2 dominantly-affects constitutive internalisation of GABABRs. Notably, the internalisation profile of R1aR2 heteromers, but not R1a homomers devoid of their ER retention motif (R1ASA), is similar to R2 homomers in heterologous systems. The internalisation of R1aASA was slowed to that of R2 by mutating a di-leucine motif in the R1 C-terminus, indicating a new role for heterodimerisation, whereby R2 subunits slow the internalization of surface GABABRs.
    [Show full text]
  • Cellular Trafficking of Nicotinic Acetylcholine Receptors
    npg Acta Pharmacol Sin 2009 Jun; 30 (6): 656–662 Review Cellular trafficking of nicotinic acetylcholine receptors Paul A ST JOHN* Department of Cell Biology and Anatomy, University of Arizona College of Medicine, Tucson, AZ 85724, USA Nicotinic acetylcholine receptors (nAChRs) play critical roles throughout the body. Precise regulation of the cellular loca- tion and availability of nAChRs on neurons and target cells is critical to their proper function. Dynamic, post-translational regulation of nAChRs, particularly control of their movements among the different compartments of cells, is an important aspect of that regulation. A combination of new information and new techniques has the study of nAChR trafficking poised for new breakthroughs. Keywords: membrane traffic; protein traffic; biosynthesis; endocytosis; endoplasmic reticulum-associated degradation Acta Pharmacologica Sinica (2009) 30: 656–662; doi: 10.1038/aps.2009.76 Introduction ways, but two particular perturbations have been especially well studied and exert their effects at least in part by altering Nicotinic acetylcholine receptors (nAChRs) mediate the trafficking of nAChRs: 1) denervation changes the total synaptic transmission in the CNS, in autonomic ganglia, and number, the distribution, and the turnover rate of nAChRs in at neuromuscular junctions and other peripheral synapses. skeletal muscle; 2) prolonged exposure to nicotine increases The functional properties of these synapses differ, but in each the total number of nAChRs in neurons. Several of the stud- case, properly functional signaling requires cellular control ies reviewed here addressed the mechanisms by which these of the number, type, and location of nAChRs. Trafficking treatments alter nAChR trafficking. Other authors in this of nAChRs – the movement of nAChRs between compart- special issue will address other aspects of the effects of nico- ments of a cell, including the cell's biosynthetic and degrada- tine on nAChRs.
    [Show full text]
  • Kainate Receptors Depress Excitatory Synaptic Transmission at CA33CA1 Synapses in the Hippocampus Via a Direct Presynaptic Action
    The Journal of Neuroscience, May 1, 2001, 21(9):2958–2966 Kainate Receptors Depress Excitatory Synaptic Transmission at CA33CA1 Synapses in the Hippocampus via a Direct Presynaptic Action Matthew Frerking,1 Dietmar Schmitz,1 Qiang Zhou,1 Joshua Johansen,2 and Roger A. Nicoll1,2 Departments of 1Cellular and Molecular Pharmacology and 2Physiology, University of California, San Francisco, California 94143-0450 Kainate receptor activation depresses synaptic release of neu- excitation and subsequent release of a neuromodulator. Pre- rotransmitter at a number of synapses in the CNS. The mech- synaptic depolarization, achieved via increasing extracellular anism underlying this depression is controversial, and both K ϩ, caused a depression of the presynaptic fiber volley and an ionotropic and metabotropic mechanisms have been sug- increase in the frequency of miniature EPSCs. Neither effect gested. We report here that the AMPA/kainate receptor ago- was observed with DA, suggesting that DA does not depress nists domoate (DA) and kainate (KA) cause a presynaptic de- transmission via a presynaptic depolarization. However, the pression of glutamatergic transmission at CA33CA1 synapses effects of DA were abolished by the G-protein inhibitors in the hippocampus, which is not blocked by the AMPA recep- N-ethylmaleimide and pertussis toxin. These results suggest tor antagonist GYKI 53655 but is blocked by the AMPA/KA that KA receptor activation depresses synaptic transmission at receptor antagonist CNQX. Neither a blockade of interneuronal this synapse via a direct, presynaptic, metabotropic action. discharge nor antagonists of several neuromodulators affect Key words: domoate; kainate; metabotropic; presynaptic; the depression, suggesting that it is not the result of indirect hippocampus; CA1 Neurotransmitter receptors in the CNS can be separated into two use-dependent depression.
    [Show full text]
  • Functional Kainate-Selective Glutamate Receptors in Cultured Hippocampal Neurons (Excitatory Amino Acid Receptors/Hippocampus) JUAN LERMA*, ANA V
    Proc. Natl. Acad. Sci. USA Vol. 90, pp. 11688-11692, December 1993 Neurobiology Functional kainate-selective glutamate receptors in cultured hippocampal neurons (excitatory amino acid receptors/hippocampus) JUAN LERMA*, ANA V. PATERNAIN, JosE R. NARANJO, AND BRITT MELLSTR6M Departamento de Plasticidad Neural, Instituto Cajal, Consejo Superior de Investigaciones Cientfficas, Avenida Doctor Arce 37, 28002-Madrid, Spain Communicated by Michael V. L. Bennett, September 15, 1993 ABSTRACT Glutamate mediates fast synaptic transmis- experiments, the regional distribution of high-affinity sion at the majority of excitatory synapses throughout the [3H]kainate binding sites does not match the AMPA receptor central nervous system by interacting with different types of distribution but corresponds well to the brain areas with high receptor channels. Cloning of glutamate receptors has pro- susceptibility to the neurotoxic actions of kainate (e.g., vided evidence for the existence of several structurally related hippocampal CA3 field) (13). However, patch-clamp record- subunit families, each composed of several members. It has ings from adult hippocampal neurons have revealed that been proposed that KA1 and KA2 and GluR-5, GluR-6, and native glutamate receptors are similar to the AMPA-type GluR-7 families represent subunit classes of high-affinity kain- recombinant glutamate receptors expressed from cDNA ate receptors and that in vivo different kainate receptor sub- clones but have failed so far to detect receptor channels ofthe types might be constructed from these subunits in heteromeric kainate type (14, 15). The only apparently high-affinity kain- assembly. However, despite some indications from autoradio- ate receptor channels have been found in the peripheral graphic studies and binding data in brain membranes, no nervous system (16, 17), although they are also activated by functional pure kainate receptors have so far been detected in AMPA.
    [Show full text]
  • (12) Patent Application Publication (10) Pub. No.: US 2005/0215521 A1 Lalji Et Al
    US 20050215521A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2005/0215521 A1 Lalji et al. (43) Pub. Date: Sep. 29, 2005 (54) MODAFINIL COMBINATION THERAPY FOR Publication Classification IMPROVING SLEEP QUALITY (51) Int. Cl.' .................. A61K 31/724; A61K 31/7008; (76) Inventors: Karim Lalji, Sudbury, MA (US); A61K 31/4164; A61K 31/195; Timothy J. Barberich, Concord, MA A61K 31/165 (US) (52) U.S. Cl. ............................ 514/58; 514/221; 514/389; 514/561; 514/557; 514/23; Correspondence Address: 514/618; 514/469 FOLEY HOAG, LLP PATENT GROUP, WORLD TRADE CENTER WEST (57) ABSTRACT 155 SEAPORT BLVD One aspect of the present invention relates to pharmaceutical BOSTON, MA 02110 (US) compositions comprising a compound that modulates the orexin System and a Sedative agent. In a preferred embodi (21) Appl. No.: 11/018,869 ment, the compound that modulates the orexin System is (22) Filed: Dec. 21, 2004 modafinil and the Sedative agent is eSZopiclone. The phar maceutical compositions of the invention are useful in the Related U.S. Application Data treatment of various sleep disorders. In addition, the present invention relates to a method of treating a patient Suffering (60) Provisional application No. 60/531,822, filed on Dec. from a sleep abnormality or insomnia comprising adminis 22, 2003. Provisional application No. 60/541,684, tering a therapeutically effective amount of a pharmaceutical filed on Feb. 4, 2004. composition of the invention. Patent Application Publication Sep. 29, 2005 Sheet 1 of 2 US 2005/0215521 A1 Figure 1 (RS)-Zopiclone D-Malic Acid Acetone Mixing/Heating Methanol Methanol-DCooling/Crystallizatio (S)-Zopiclone D-Malate See Methanol Filtration/Washing Mother Liquors/Washes -Ge IPC (S)-Zopiclone D-Malate Patent Application Publication Sep.
    [Show full text]
  • Kainate Receptor-Mediated Depression of Glutamate Release
    Article Kainate Receptor‐Mediated Depression of Glutamate Release Involves Protein Kinase A in the Cerebellum Rafael Falcón‐Moya, Pilar Losada‐Ruiz and Antonio Rodríguez‐Moreno * Laboratorio de Neurociencia Celular y Plasticidad, Departamento de Fisiología, Anatomía y Biología Celular, Universidad Pablo de Olavide, ES‐41013 Sevilla, Spain * Correspondence: [email protected]; Tel: +34‐95497‐7393 Received: 20 July 2019; Accepted: 23 August 2019; Published: 23 August 2019 Abstract: Kainate (KA) receptors (KAR) have important modulatory roles of synaptic transmission. In the cerebellum, the action mechanisms of KAR‐mediated glutamatergic depression are unknown. We studied these mechanisms by recording evoked excitatory postsynaptic currents (eEPSCs) from cerebellar slices using the whole‐cell configuration of the patch‐clamp technique. We observed that 3 μM KA decreased the amplitude of eEPSCs and increased the number of failures at the synapses established between parallel fibers (PF) and Purkinje neurons, and the effect was antagonized by NBQX under the condition where AMPA receptors were previously blocked. The inhibition of protein kinase A (PKA) suppressed the effect of KAR activation on eEPSC, and effect was not prevented by protein kinase C inhibitors. Furthermore, in the presence of Pertussis toxin, the depression of glutamate release mediated by KAR activation was prevented, invoking the participation of a Gi/o protein in this modulation. Finally, the KAR‐mediated depression of glutamate release was not prevented by blocking calcium‐permeable KARs or by treatments that affect calcium release from intracellular stores. We conclude that KARs present at these synapses mediate an inhibition of glutamate release through a mechanism that involves the activation of G‐protein and protein kinase A.
    [Show full text]