DOCSLIB.ORG

Glutamate NMDA Receptors in Pathophysiology And

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text

Load more

® Postepy Hig Med Dosw (online), 2011; 65: 338-346 www.phmd.pl e-ISSN 1732-2693 Review Received: 2011.02.07 Accepted: 2011.05.11 Glutamate NMDA receptors in pathophysiology and Published: 2011.06.07 pharmacotherapy of selected nervous system diseases Rola receptorów NMDA w patofizjologii i farmakoterapii wybranych chorób układu nerwowego Łukasz Dobrek, Piotr Thor Department of Pathophysiology, Jagiellonian University Medical College Cracow, Poland Summary Glutamate is the basic excitatory neurotransmitter acting via N-methyl-D-aspartate receptors (NMDARs). It co-regulates many important physiological functions, including learning, memo- ry, and behaviour. An excess of glutamate, as well as NMDAR over-activity, produce pathologi- cal effects. Glutamate-related neurotoxicity is involved in the pathogenesis of many neurological conditions. This article briefly describes the role of the glutamate system in the pathophysiology of brain ischemia, selected neurodegenerative disorders, and schizophrenia. It also reviews the current and potential future status of agents targeting NMDARs in neuropsychopharmacology. Key words: glutamate • NMDA receptors (NMDARs) • excitotoxicity • NMDAR antagonists Streszczenie Glutaminian jest podstawowym neuroprzekaźnikiem pobudzającym, który działa na receptory NMDA. Związek ten jest współodpowiedzialny za regulowanie wielu ważnych fizjologicznych funkcji, wliczając w to uczenie się, pamięć i zachowanie. Nadmiar glutaminianu i nadaktywność receptorów NMDARs wywołuje patologiczne zmiany. Zjawisko neurotoksyczności zależnej od glutaminianu bierze udział w patogenezie wielu zaburzeń neurologicznych. Artykuł pokrótce opisuje rolę glutaminianu w patofizjologii udaru niedokrwiennego mózgu, wybranych chorób neurodegeneracyjnych i schizofrenii oraz omawia obecne i potencjalne znaczenie leków działa- jących na receptory glutaminergiczne w neuropsychofarmakologii. Słowa kluczowe: glutaminian • receptory NMDA • neurotoksyczność glutaminianu • antagoniści receptora NMDA Full-text PDF: http://www.phmd.pl/fulltxt.php?ICID=946637 Word count: 4925 Tables: 1 Figures: 1 References: 28 Author’s address: Łukasz Dobrek, M.D., Department of Pathophysiology, Jagiellonian University Medical College, Czysta Street 18, 31-121 Cracow, Poland; e-mail: [email protected] 338 ® Postepy Hig Med Dosw (online), 2011; 65 338 Dobrek Ł. and Thor P. – Glutamate NMDA receptors in pathophysiology… Abbreviations: AD – Alzheimer’s disease; ALS – Amyotrophic lateral sclerosis; AMPAR – a-amino-3-hydroxy-5- methylisoxazole-4-propionic acid receptor; CJD – Creutzfeld-Jacob disease; EAATs – Excitatory aminoacids transporters; GABA – g-aminobutyric acid; glyT1 – glycine transporter 1; HD – Huntington disease; KAR – Kainate receptor; LTD – Long term depression; LTP – Long term potentiation; MAPK – Mitogen activated protein kinase; NMDAR – N-methyl-D-aspartate receptor; PD – Parkinson disease; PSD – Postsynaptic density; TBI – Traumatic brain injury. 1. GLUTAMATE RECEPTORS Considering the NMDAR molecular structure, one may surmise that they have a common membrane topology In mammalian central nervous system synapses, glutama- with a large extracellular N-terminus, a membrane region te is the major neurotransmitter mediating excitatory neu- composed of three transmembrane segments, and differ rotransmission. It is released from presynaptic vesicles, in the cytoplasmic C-terminus, depending on the vario- diffuses across the synaptic cleft, and acts on both me- us subunits, which interacts with numerous intracellular tabotropic and ionotropic glutamate receptors located in proteins [3,22]. the presynaptic terminals and postsynaptic membranes of the brain and spinal neurons. Three ionotropic glutamate Opening of the channel pore by NMDAR requires the si- receptor subtypes can be distinguished, and they are na- multaneous binding of the major agonist – glutamate (which med according to their agonists: NMDAR (N-methyl-D- play a neurotransmitter role) and the co-agonist – glyci- aspartate receptor), AMPAR (a-amino-3-hydroxy-5-me- ne (or D-serine, which act as modulators). The glutama- thylisoxazole-4-propionic acid receptor) and KAR (kainate te binding site is located on the NR2 subunit, whereas the receptor). NMDARs are composed of protein complexes glycine binding site is located on the NR1 subunit. After which form an intrinsic ion channel, permeable to mono- presynaptic glutamate release, and with sufficient glycine valent cations (including Na+ and K+), and bivalent ones concentration in the synaptic cleft, NMDAR activation takes (mostly Ca2+). We also know of a metabotropic glutamate place. When the membrane is depolarised, the voltage-de- receptor coupled to a G intrinsic membrane protein [12,13]. pendent Mg2+ block is removed from the channel interior, allowing for ion to enter. By contrast, AMPARs, composed NMDARs contain four subunits which are a combination of: of various combinations of four subunits ( GluR1-GluR4) NR1, NR2, and NR3, (encoded by genes GRIN1, GRIN2A-D, are permeable to Ca2+ only in the absence of the GluR2 GRIN3A-B, respectively). There is consensus that NMDARs element [3,12,13,22]. are tetramers composed of two NR1 subunits and two NR2 subunits, less commonly including NR3 subunits. NR1 sub- The general scheme of NMDA receptor structure together units exhibit basic NMDAR features and disruption of NR1 with the potential sites for pharmacological action descri- genes abolishes NMDAR responses. This demonstrates that bed below presents figure 1. NR1 subunits are rather essential. There are eight different NR1 elements, generated by alternative splicing of a single NMDARs can be divided into two classes according to the- gene. Four (A-D) NR2 compounds can be distinguished, ir conductance properties: high conductance channels (bu- located in various brain regions and playing a modulatory ilt from NR2A or NR2B) and low conductance ones (for- role in regards to NMDARs. It has been shown that the com- med by NR2C and NR2D) with reduced sensitivity to Mg2+ bination of NR1 with different NR2 subunits results in di- block. An influx of extracellular calcium initiates complex verse electrophysiological and pharmacological responses. signalling pathways compromised of the mitogen-activa- NR1 and NR2A are ubiquitous, NR2B occurs in the fore- ted protein kinase (MAPK) superfamily that transduces brain, NR2C in the cerebellum, with NR2D being the rarest. excitatory signals across the neuron. Taking into conside- There is a binding place in the channel pore for Mg2+, and ration in vitro substances, MAPKs have been also called at resting membrane potential, Mg2+ is attached to this bin- microtubule associated protein-2 kinase (MAP-2 kinase), ding site, blocking ion flow through the channel [3,12,22]. myelin basic protein kinase (MBP kinase), ribosomal S6 protein kinase (RSK-kinase) and epidermal growth factor Generally, NMDARs occur in many but not all cerebral (EGF) receptor threonine kinase (ERT kinase). MAPK ac- cortex neurons and some cortical astrocytes. They are mo- tivation was observed in response to NMDARs stimulation, stly located on dendrites. Immunocytochemical studies starting with tyrosine phosphorylation of MAPKs. An ad- have revealed that NMDARs are less frequently found in ditional class of kinases, named MAP kinase kinases and the 4th layer than in layers 2 to 3 and 5 to 6, where they are MAPK kinase kinases (MAPKK kinases), are then excited, preferentially expressed by pyramidal neurons. This is in through an intermediate step involving MAPK stimulation. agreement with the notion that afferent glutaminergic in- Usually, three MAPKs are distinguished: extracellular si- put reaches the cerebral cortex through the thalamocortical gnal-regulated kinase-1 (ERK1 and 2), the Jun N-terminal pathway, formed by axons of the 4th layer. NMDA recep- kinases (JNKs) activating Jun transcription factor, and the tors are localised in the postsynaptic membrane, organised p38 MAPKs. The two last ones are called stress-activated by a multi-protein structure called the postsynaptic densi- kinases (SAPKs), because they are stimulated by stressful ty (PSD). These receptors, however, are mobile and move conditions. Consequently, the transcription factor cAMP- between the synaptic and extra-synaptic pools. The PSD -Ca2+ response element-binding protein (CREB) causes is defined as a type of postsynaptic membrane that conta- the expression of genes that encode brain-derived neuro- ins high concentrations of glutamate receptors, ion chan- trophic factor (BDNF) and other factors promoting neuro- nels, kinases, phosphatases and associated proteins [2,13]. nal survival and activity [5,9,24,27]. Detailed information 339 Postepy Hig Med Dosw (online), 2011; tom 65: 338-346 Fig. 1. NMDA receptor scheme and selected NMDAR- based pharmacological strategies for treatment voltage gated [12,22] channels inhibitors presynaptic neuron neurotransmitter glia Glycine NR1 site glutamate reuptake Glutamate NR2 site enhancers EAAT NR NR 1 2 tetrameric NMDA receptor NMDAR antagonists signalling pathway NR1 subunit-kinase, signalling protein phospatase modulators NR2 subunit-scaold protein, signalling enzyme MAPK gene transcription postsynaptic neuron concerning NMDAR and MAPK signalling is given in an 2. GLUTAMATE AND SYNAPTIC PLASTICITY excellent review prepared by Haddad [9]. The glutamate system is thought to be involved in learning AMPARs, similar to NMDARs, couple to the MAPK pa- and memory processes. It is associated with the phenomenon thways through similar sets
Recommended publications
  • Opioid-Induced Hyperalgesia in Humans Molecular Mechanisms and Clinical Considerations

    Opioid-Induced Hyperalgesia in Humans Molecular Mechanisms and Clinical Considerations

    SPECIAL TOPIC SERIES Opioid-induced Hyperalgesia in Humans Molecular Mechanisms and Clinical Considerations Larry F. Chu, MD, MS (BCHM), MS (Epidemiology),* Martin S. Angst, MD,* and David Clark, MD, PhD*w treatment of acute and cancer-related pain. However, Abstract: Opioid-induced hyperalgesia (OIH) is most broadly recent evidence suggests that opioid medications may also defined as a state of nociceptive sensitization caused by exposure be useful for the treatment of chronic noncancer pain, at to opioids. The state is characterized by a paradoxical response least in the short term.3–14 whereby a patient receiving opioids for the treatment of pain Perhaps because of this new evidence, opioid may actually become more sensitive to certain painful stimuli. medications have been increasingly prescribed by primary The type of pain experienced may or may not be different from care physicians and other patient care providers for the original underlying painful condition. Although the precise chronic painful conditions.15,16 Indeed, opioids are molecular mechanism is not yet understood, it is generally among the most common medications prescribed by thought to result from neuroplastic changes in the peripheral physicians in the United States17 and accounted for 235 and central nervous systems that lead to sensitization of million prescriptions in the year 2004.18 pronociceptive pathways. OIH seems to be a distinct, definable, One of the principal factors that differentiate the use and characteristic phenomenon that may explain loss of opioid of opioids for the treatment of pain concerns the duration efficacy in some cases. Clinicians should suspect expression of of intended use.
  • A Guide to Glutamate Receptors

    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
  • Glycine Activated Ion Channel Subunits Encoded by Ctenophore

    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.
  • Role of a Hippocampal Src-Family Kinase-Mediated Glutamatergic Mechanism in Drug Context-Induced Cocaine Seeking

    Role of a Hippocampal Src-Family Kinase-Mediated Glutamatergic Mechanism in Drug Context-Induced Cocaine Seeking

    Neuropsychopharmacology (2013) 38, 2657–2665 & 2013 American College of Neuropsychopharmacology. All rights reserved 0893-133X/13 www.neuropsychopharmacology.org Role of a Hippocampal Src-Family Kinase-Mediated Glutamatergic Mechanism in Drug Context-Induced Cocaine Seeking 1 1 1 1 ,1 Xiaohu Xie , Amy A Arguello , Audrey M Wells , Andrew M Reittinger and Rita A Fuchs* 1 Department of Psychology, University of North Carolina, Chapel Hill, NC, USA Glutamatergic neurotransmission in the dorsal hippocampus (DH) is necessary for drug context-induced reinstatement of cocaine- seeking behavior in an animal model of drug relapse. Furthermore, in vitro studies suggest that the Src family of tyrosine kinases critically regulates glutamatergic cellular functions within the DH. Thus, Src-family kinases in the DH may similarly control contextual cocaine- seeking behavior. To test this hypothesis, rats were trained to lever press for un-signaled cocaine infusions in a distinct context followed by extinction training in a different context. Cocaine-seeking behavior (non-reinforced active lever pressing) was then assessed in the previously cocaine-paired and extinction contexts after AP5 (N-methyl-D-aspartate glutamate (NMDA) receptor (NMDAR) antagonist; 0.25 or 2.5 mg/0.5 ml/hemisphere), PP2 (Src-family kinase inhibitor; 6.25 or 62.5 ng/0.5 ml/hemisphere), Ro25-6981 (NR2B subunit- containing NMDAR antagonist; 0.2 or 2 mg/0.5 ml/hemisphere), or vehicle administration into the DH. Administration of AP5, PP2, or Ro25-6981 into the DH dose-dependently impaired drug context-induced reinstatement of cocaine-seeking behavior relative to vehicle, without altering instrumental behavior in the extinction context or food-reinforced instrumental responding and general motor activity in control experiments.
  • Profil D'effets Indésirables Des Antagonistes R-NMDA

    Profil D'effets Indésirables Des Antagonistes R-NMDA

    Profil d’effets indésirables des antagonistes R-NMDA : analyse de clusters des signaux de disproportionnalité extraits de Vigibase® Nhan-Taï Pierre Ly To cite this version: Nhan-Taï Pierre Ly. Profil d’effets indésirables des antagonistes R-NMDA : analyse de clusters des signaux de disproportionnalité extraits de Vigibase®. Sciences pharmaceutiques. 2019. dumas- 03039996 HAL Id: dumas-03039996 https://dumas.ccsd.cnrs.fr/dumas-03039996 Submitted on 4 Dec 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. AVERTISSEMENT Ce document est le fruit d'un long travail approuvé par le jury de soutenance et mis à disposition de l'ensemble de la communauté universitaire élargie. Il n’a pas été réévalué depuis la date de soutenance. Il est soumis à la propriété intellectuelle de l'auteur. Ceci implique une obligation de citation et de référencement lors de l’utilisation de ce document. D’autre part, toute contrefaçon, plagiat, reproduction illicite encourt une poursuite pénale. Contact au SID de Grenoble : [email protected] LIENS LIENS Code
  • Tinnitus Hopes Put to Sleep by Latest Auris Failure

    Tinnitus Hopes Put to Sleep by Latest Auris Failure

    March 14, 2018 Tinnitus hopes put to sleep by latest Auris failure Madeleine Armstrong Ketamine is best known as a horse tranquiliser or a recreational drug, but it has also been proposed as a treatment for various disorders from depression to Alzheimer’s. Hopes of developing the drug in tinnitus have been dashed by the failure of Auris’s Keyzilen in a second phase III trial. As well as leaving Auris’s future looking bleak – Keyzilen is the second of its phase III candidates to flunk in four months – the setback could also be bad news for the sparse tinnitus pipeline. According to EvaluatePharma there is only one other candidate in active clinical development, Otonomy’s OTO-313, and this uses the same mechanism of action as Keyzilen (see table below). Tinnitus pipeline Generic Project Company Pharma class Trial(s) Notes name Phase III Auris Esketamine TACTT2 Keyzilen NMDA antagonist Failed Aug 2016 Medical hydrochloride (NCT01803646) TACTT3 Failed Mar 2018 (NCT02040194) Phase I OTO- Phase I/II trial to OTO-311 abandoned in Otonomy NMDA antagonist Gacyclidine 313 start H1 2019 favour of this formulation Preclinical Auris AM-102 Undisclosed - - Medical KCNQ2 Knopp Kv7 potassium - - Program Biosciences channel modulator Source: EvaluatePharma. Both projects are psychoactive drugs targeting the NMDA receptor. Tinnitus is commonly caused by loud noise and resulting damage to the sensory hair cells in the cochlea. Initial trauma to the inner ear has been shown to trigger excess production of glutamate, which leads to the hyperactivation of NMDA receptors and, in turn, cell death. Blocking the NMDA receptor could therefore have a protective effect – but it is unclear how this mechanism would work once the damage to hair cells had been done.
  • (12) United States Patent (10) Patent No.: US 9.435,817 B2 Benchikh Et Al

    (12) United States Patent (10) Patent No.: US 9.435,817 B2 Benchikh Et Al

    USOO9435817B2 (12) United States Patent (10) Patent No.: US 9.435,817 B2 Benchikh et al. (45) Date of Patent: Sep. 6, 2016 (54) DETECTION OF SYNTHETIC OTHER PUBLICATIONS CANNABINOIDS C. V. Rao, “Immunology. A textbook”. Alpha Science Internatl. Ltd., 2005, pp. 63, 69-71.* (75) Inventors: Elouard Benchikh, Crumlin (GB); Weissman et al., “Cannabimimetic activity from CP-47,497, a Stephen Peter Fitzgerald, Crumlin derivative of 3-phenylcyclohexanol.” J. Pharmacol. Exp. Ther. (GB); Paul John Innocenzi, Crumlin 1982, vol. 223, No. 2, pp. 516-523.* (GB); Philip Andrew Lowry, Crumlin Wild, “The Immunoassay Handbook.” Third Ed., Elsevier, 2005, (GB); Ivan Robert McConnell, pp. 255-256.* Crumlin (GB) Melvin et al., “A cannabinoid derived prototypical analgesic,” J. Med. Chem., 1984, vol. 27, No. 1, pp. 67-71.* Dresen, S. et al., “Monitoring of Herbal Mixtures Potentially (73) Assignee: Randox Laboratories Limited, Containing Synthetic Cannabinoids as Psychoactive Compounds.” Crumlin (GB) J. Mass. Spectrometry, 2010, pp. 1186-1194, vol. 45. Goodrow, M.H. et al., “Strategies for Immunoassay Hapten (*) Notice: Subject to any disclaimer, the term of this Design,” in Immunoanalysis of Agrochemicals; Nelson, J. et al., patent is extended or adjusted under 35 ACS Symposium Series, 1995, Chapter 9, pp. 119-139, vol. 586. U.S.C. 154(b) by 590 days. Hudson, S. et al., “Use of High-Resolution Accurate Mass Spec trometry to Detect Reported and Previously Unreported Can (21) Appl. No.: 13/585,630 nabinomimetics in Herbal High Products,” J. Anal. Toxicol., 2010, pp. 252-260, vol. 34. Huffman, J. et al., “1-Pentyl-3-phenylacetylindoles, a New Class of (22) Filed: Aug.
  • Interactions Between Nitrous Oxide and Tissue Plasminogen Activator in a Rat Model of Thromboembolic Stroke

    Interactions Between Nitrous Oxide and Tissue Plasminogen Activator in a Rat Model of Thromboembolic Stroke

    Interactions between Nitrous Oxide and Tissue Plasminogen Activator in a Rat Model of Thromboembolic Stroke Benoît Haelewyn, Ph.D.,* He´le` ne N. David, Ph.D.,† Nathalie Colloc’h, Ph.D., D.Sc.,‡ Denis G. Colomb, Jr., Ph.D.,§ Jean-Jacques Risso, Ph.D., D.Sc.,ʈ Jacques H. Abraini, Ph.D., D.Sc., Psy.D.# Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/115/5/1044/452771/0000542-201111000-00027.pdf by guest on 25 September 2021 ABSTRACT What We Already Know about This Topic • Whether nitrous oxide, like xenon, reduces of ischemic brain Background: Preclinical evidence in rodents has suggested damage in the setting of thrombolysis for thromboembolic that inert gases, such as xenon or nitrous oxide, may be prom- stroke is unknown. ising neuroprotective agents for treating acute ischemic stroke. This has led to many thinking that clinical trials could be initiated in the near future. However, a recent study has What This Article Tells Us That Is New shown that xenon interacts with tissue-type plasminogen ac- • In rats, when administrated during the ischemic period, nitrous tivator (tPA), a well-recognized approved therapy of acute oxide dose-dependently inhibited tPa-induced thrombolysis and subsequent reduction of ischemic brain damage. How- * Research Engineer and Head, Universite´ de Caen - Basse Nor- ever, in contrast to xenon, postischemic nitrous oxide in- mandie, Centre Universitaire de Ressources Biologiques, Caen, France. creased brain hemorrhage and barrier dysfunction. † Research Scientist, Universite´ Laval, Centre Hospitalier Universitaire Affilie´Hoˆtel-Dieu Le´vis, Le´vis, Que´bec, Canada; Universite´ Laval, Cen- tre de Recherche Universite´ Laval Robert-Giffard, Que´bec, Que´bec, Canada.
  • Interplay Between Gating and Block of Ligand-Gated Ion Channels

    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.
  • From NMDA Receptor Hypofunction to the Dopamine Hypothesis of Schizophrenia J

    From NMDA Receptor Hypofunction to the Dopamine Hypothesis of Schizophrenia J

    REVIEW The Neuropsychopharmacology of Phencyclidine: From NMDA Receptor Hypofunction to the Dopamine Hypothesis of Schizophrenia J. David Jentsch, Ph.D., and Robert H. Roth, Ph.D. Administration of noncompetitive NMDA/glutamate effects of these drugs are discussed, especially with regard to receptor antagonists, such as phencyclidine (PCP) and differing profiles following single-dose and long-term ketamine, to humans induces a broad range of exposure. The neurochemical effects of NMDA receptor schizophrenic-like symptomatology, findings that have antagonist administration are argued to support a contributed to a hypoglutamatergic hypothesis of neurobiological hypothesis of schizophrenia, which includes schizophrenia. Moreover, a history of experimental pathophysiology within several neurotransmitter systems, investigations of the effects of these drugs in animals manifested in behavioral pathology. Future directions for suggests that NMDA receptor antagonists may model some the application of NMDA receptor antagonist models of behavioral symptoms of schizophrenia in nonhuman schizophrenia to preclinical and pathophysiological research subjects. In this review, the usefulness of PCP are offered. [Neuropsychopharmacology 20:201–225, administration as a potential animal model of schizophrenia 1999] © 1999 American College of is considered. To support the contention that NMDA Neuropsychopharmacology. Published by Elsevier receptor antagonist administration represents a viable Science Inc. model of schizophrenia, the behavioral and neurobiological KEY WORDS: Ketamine; Phencyclidine; Psychotomimetic; widely from the administration of purportedly psychot- Memory; Catecholamine; Schizophrenia; Prefrontal cortex; omimetic drugs (Snyder 1988; Javitt and Zukin 1991; Cognition; Dopamine; Glutamate Jentsch et al. 1998a), to perinatal insults (Lipska et al. Biological psychiatric research has seen the develop- 1993; El-Khodor and Boksa 1997; Moore and Grace ment of many putative animal models of schizophrenia.
  • United States Patent (19) 11 Patent Number: 5,902,815 Olney Et Al

    United States Patent (19) 11 Patent Number: 5,902,815 Olney Et Al

    USOO5902815A United States Patent (19) 11 Patent Number: 5,902,815 Olney et al. (45) Date of Patent: May 11, 1999 54 USE OF 5HT2A SEROTONIN AGONISTS TO Hougaku, H. et al., “Therapeutic effect of lisuride maleate on PREVENT ADVERSE EFFECTS OF NMDA post-stroke depression” Nippon Ronen Igakkai ZaSShi 31: RECEPTOR HYPOFUNCTION 52-9 (1994) (abstract). Kehne, J.H. et al., “Preclinical Characterization of the Poten 75 Inventors: John W. Olney, Ladue; Nuri B. tial of the Putative Atypical Antipsychotic MDL 100,907 as Farber, University City, both of Mo. a Potent 5-HT2A Antagonist with a Favorable CNS Saftey Profile.” The Journal of Pharmacology and Experimental 73 Assignee: Washington University, St. Louis, Mo. Therapuetics 277: 968–981 (1996). Maurel-Remy, S. et al., “Blockade of phencyclidine-induced 21 Appl. No.: 08/709,222 hyperlocomotion by clozapine and MDL 100,907 in rats reflects antagonism of 5-HT2A receptors' European Jour 22 Filed: Sep. 3, 1996 nal of Pharmacology 280: R9–R11 (1995). 51) Int. Cl. ........................ A61K 31/445; A61K 31/54; Olney, J.W., et al., “NMDAantagonist neurotoxicity: Mecha A61K 31/135 nism and prevention,” Science 254: 1515–1518 (1991). 52 U.S. Cl. .......................... 514/285; 514/315; 514/318; Olney, J.W., et al., “Glutamate receptor dysfunction and 514/646 schizophrenia.” Arch. Gen. Psychiatry 52:998-1007 (1995). 58 Field of Search ............................. 514/285; 314/315, Pulvirenti, L. et al., “Dopamine receptor agonists, partial 314/318, 646 agonists and psychostimulant addiction' Trends Pharmacol Sci 15: 374-9 (1994). 56) References Cited Robles, R.G. et al., “Natriuretic Effects of Dopamine Agonist Drugs in Models of Reduced Renal Mass” Journal of U.S.
  • Cellular Trafficking of Nicotinic Acetylcholine Receptors

    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.