Mechanism of Action of Ethylenediamine On
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GABAA Transmission Is a Critical Step in the Process of Triggering Homeostatic Increases in Quantal Amplitude
GABAA transmission is a critical step in the process of triggering homeostatic increases in quantal amplitude Jennifer C. Wilhelm and Peter Wenner* Department of Physiology, Emory University School of Medicine, Atlanta, GA 30322 Communicated by Lynn T. Landmesser, Case Western Reserve University, Cleveland, OH, June 23, 2008 (received for review March 1, 2008) When activity levels are altered over days, a network of cells is models suggests that reducing network activity produces a corre- capable of recognizing this perturbation and triggering several dis- sponding reduction in cellular spiking activity, thereby reducing tinct compensatory changes that should help to recover and maintain intracellular calcium levels in a postsynaptic cell. In this model, the original activity levels homeostatically. One feature commonly which we will refer to as the cell activity model, the postsynaptic cell observed after activity blockade has been a compensatory increase in senses changes in intracellular calcium levels as a measure of altered excitatory quantal amplitude. The sensing machinery that detects activity and triggers compensatory changes in mPSC amplitude. altered activity levels is a central focus of the field currently, but thus However, the studies that have inspired this model not only block far it has been elusive. The vast majority of studies that reduce spiking activity, they also block or reduce neurotransmitter binding network activity also reduce neurotransmission. We address the to its receptor and any associated downstream signaling cascades. possibility that reduced neurotransmission can trigger increases in Thus, it remains possible that neurotransmission is a critical step in quantal amplitude. In this work, we blocked glutamatergic or GABAA the sensing process that triggers changes in quantal amplitude. -
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. -
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. -
Bicuculline and Gabazine Are Allosteric Inhibitors of Channel Opening of the GABAA Receptor
The Journal of Neuroscience, January 15, 1997, 17(2):625–634 Bicuculline and Gabazine Are Allosteric Inhibitors of Channel Opening of the GABAA Receptor Shinya Ueno,1 John Bracamontes,1 Chuck Zorumski,2 David S. Weiss,3 and Joe Henry Steinbach1 Departments of 1Anesthesiology and 2Psychiatry, Washington University School of Medicine, St. Louis, Missouri 63110, and 3University of Alabama at Birmingham, Neurobiology Research Center and Department of Physiology and Biophysics, Birmingham, Alabama 35294-0021 Anesthetic drugs are known to interact with GABAA receptors, bicuculline only partially blocked responses to pentobarbital. both to potentiate the effects of low concentrations of GABA and These observations indicate that the blockers do not compete to directly gate open the ion channel in the absence of GABA; with alphaxalone or pentobarbital for a single class of sites on the however, the site(s) involved in direct gating by these drugs is not GABAA receptor. Finally, at receptors containing a1b2(Y157S)g2L known. We have studied the ability of alphaxalone (an anesthetic subunits, both bicuculline and gabazine showed weak agonist steroid) and pentobarbital (an anesthetic barbiturate) to directly activity and actually potentiated responses to alphaxalone. These activate recombinant GABAA receptors containing the a1, b2, and observations indicate that the blocking drugs can produce allo- g2L subunits. Steroid gating was not affected when either of two steric changes in GABAA receptors, at least those containing this mutated b2 subunits [b2(Y157S) and b2(Y205S)] are incorporated mutated b2 subunit. We conclude that the sites for binding ste- into the receptors, although these subunits greatly reduce the roids and barbiturates do not overlap with the GABA-binding site. -
Metabolic and Homeostatic Changes In
University of Dundee Metabolic and Homeostatic Changes in Seizures and Acquired Epilepsy-Mitochondria, Calcium Dynamics and Reactive Oxygen Species Kovac, Stjepana; Dinkova Kostova, Albena T; Herrmann, Alexander M; Melzer, Nico; Meuth, Sven G; Gorji, Ali Published in: International Journal of Molecular Sciences DOI: 10.3390/ijms18091935 Publication date: 2017 Licence: CC BY Document Version Publisher's PDF, also known as Version of record Link to publication in Discovery Research Portal Citation for published version (APA): Kovac, S., Dinkova Kostova, A. T., Herrmann, A. M., Melzer, N., Meuth, S. G., & Gorji, A. (2017). Metabolic and Homeostatic Changes in Seizures and Acquired Epilepsy-Mitochondria, Calcium Dynamics and Reactive Oxygen Species. International Journal of Molecular Sciences, 18(9), 1-19. [1935]. https://doi.org/10.3390/ijms18091935 General rights Copyright and moral rights for the publications made accessible in Discovery Research Portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. • Users may download and print one copy of any publication from Discovery Research Portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain. • You may freely distribute the URL identifying the publication in the public portal. Take down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Download date: 29. Sep. 2021 International Journal of Molecular Sciences Review Metabolic and Homeostatic Changes in Seizures and Acquired Epilepsy—Mitochondria, Calcium Dynamics and Reactive Oxygen Species Stjepana Kovac 1,*, Albena T. -
Ion Channels
UC Davis UC Davis Previously Published Works Title THE CONCISE GUIDE TO PHARMACOLOGY 2019/20: Ion channels. Permalink https://escholarship.org/uc/item/1442g5hg Journal British journal of pharmacology, 176 Suppl 1(S1) ISSN 0007-1188 Authors Alexander, Stephen PH Mathie, Alistair Peters, John A et al. Publication Date 2019-12-01 DOI 10.1111/bph.14749 License https://creativecommons.org/licenses/by/4.0/ 4.0 Peer reviewed eScholarship.org Powered by the California Digital Library University of California S.P.H. Alexander et al. The Concise Guide to PHARMACOLOGY 2019/20: Ion channels. British Journal of Pharmacology (2019) 176, S142–S228 THE CONCISE GUIDE TO PHARMACOLOGY 2019/20: Ion channels Stephen PH Alexander1 , Alistair Mathie2 ,JohnAPeters3 , Emma L Veale2 , Jörg Striessnig4 , Eamonn Kelly5, Jane F Armstrong6 , Elena Faccenda6 ,SimonDHarding6 ,AdamJPawson6 , Joanna L Sharman6 , Christopher Southan6 , Jamie A Davies6 and CGTP Collaborators 1School of Life Sciences, University of Nottingham Medical School, Nottingham, NG7 2UH, UK 2Medway School of Pharmacy, The Universities of Greenwich and Kent at Medway, Anson Building, Central Avenue, Chatham Maritime, Chatham, Kent, ME4 4TB, UK 3Neuroscience Division, Medical Education Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, UK 4Pharmacology and Toxicology, Institute of Pharmacy, University of Innsbruck, A-6020 Innsbruck, Austria 5School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, BS8 1TD, UK 6Centre for Discovery Brain Science, University of Edinburgh, Edinburgh, EH8 9XD, UK Abstract The Concise Guide to PHARMACOLOGY 2019/20 is the fourth in this series of biennial publications. The Concise Guide provides concise overviews of the key properties of nearly 1800 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. -
Interactions Between Ethanol and the Endocannabinoid System at Gabaergic Synapses on Basolateral Amygdala Principal Neurons
Alcohol 49 (2015) 781e794 Contents lists available at ScienceDirect Alcohol journal homepage: http://www.alcoholjournal.org/ Interactions between ethanol and the endocannabinoid system at GABAergic synapses on basolateral amygdala principal neurons Giuseppe Talani a,b, David M. Lovinger a,* a Section on Synaptic Pharmacology, Laboratory for Integrative Neuroscience, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA b Institute of Neuroscience, National Research Council, Monserrato, Cagliari, Italy article info abstract Article history: The basolateral amygdala (BLA) plays crucial roles in stimulus value coding, as well as drug and alcohol Received 14 April 2015 dependence. Ethanol alters synaptic transmission in the BLA, while endocannabinoids (eCBs) produce Received in revised form presynaptic depression at BLA synapses. Recent studies suggest interactions between ethanol and eCBs 11 August 2015 that have important consequences for alcohol drinking behavior. To determine how ethanol and eCBs Accepted 25 August 2015 interact in the BLA, we examined the physiology and pharmacology of GABAergic synapses onto BLA pyramidal neurons in neurons from young rats. Application of ethanol at concentrations relevant to intoxication increased, in both young and adult animals, the frequency of spontaneous and miniature Keywords: Alcohol GABAergic inhibitory postsynaptic currents, indicating a presynaptic site of ethanol action. Ethanol did CB1 receptor not potentiate sIPSCs during inhibition of adenylyl cyclase while still exerting its effect during inhibition Synapse of protein kinase A. Activation of type 1 cannabinoid receptors (CB1) in the BLA inhibited GABAergic Inhibition transmission via an apparent presynaptic mechanism, and prevented ethanol potentiation. Surprisingly, Arachidonoyl ethanolamide ethanol potentiation was also prevented by CB1 antagonists/inverse agonists. -
Investigating the Neural Circuits That Control Cataplexy
Investigating the Neural Circuits that Control Cataplexy by Zoltán Torontali A thesis submitted in conformity with the requirements for the degree of Doctor of Philosophy Graduate Department of Cell & Systems Biology University of Toronto © Copyright by Zoltán Torontali 2019 Investigating the Neural Circuits that Mediate Cataplexy Zoltan Torontali Doctor of Philosophy Department of Cell & Systems Biology University of Toronto 2019 Abstract In this thesis I explored a long-standing hypothesis that the paralysis occurring during REM sleep and cataplexy share a common neural mechanism. Cataplexy, a debilitating symptom of narcolepsy, is the abrupt onset of skeletal muscle paralysis during wakefulness. Under normal conditions, neurons of the sublaterodorsal tegmental region have been shown to be active during REM sleep and either activate GABA/glycine neurons of the ventral medulla or inhibitory interneurons in the spinal cord which in turn silences motoneurons and results in REM sleep muscle paralysis. The mechanism mediating the paralysis of cataplexy has not been fully characterized but is hypothesized to result from the abnormal activation of SLD neurons during wakefulness. First, I investigated if activation of all cells in the SLD nucleus could trigger cataplexy in wildtype (hypocretin-intact) mice and narcoleptic (hypocretin knockout) mice. Next, I investigated if glutamatergic, VGLUT2-expressing, neurons of the SLD were the cellular phenotype responsible for triggering cataplexy in wildtype and narcoleptic mice models. This final investigation required the development of a new hypocretin knockout mouse line (hypocretin-/-, VGLUT2-Cre mice). This new model is scientifically important as it provides an innovative toolkit for neuroscientists to examine the role of glutamatergic cell populations throughout the brain of mice with a narcolepsy phenotype. -
A Acetylcholine Anticholinergic Drugs, 49 Cholinergic Wake-Promoting
Index A C Acetylcholine Cataplexy anticholinergic drugs, 49 GHB, 37 cholinergic wake-promoting system, 48 narcolepsy type 1, 215 cholinesterase inhibitors, 48–49 narcolepsy type 2, 215 milameline, 49 sleep-promoting orexinergic inhibitors, 46 nicotine, 49 SXB, 238–240 receptors, 48 tricyclic antidepressants, 253 sleep-promoting cholinergic Cell replacement therapy, 253 inhibitors, 49 Central sleep apnea (CSA) syndrome, 76 Adenosine Cheyne–Stokes breathing (CSB), 76 adenosine-mediated sleep-promoting Cholinesterase inhibitors system, 41 donepezil, 49 receptors, 42 physostigmine, 48 sleep-promoting adenosine receptor Chronic insomnia agonists, 42 dose discrimination, lack of, 168 wake-promoting adenosine receptor psychiatric comorbidities, 169 antagonists, 42 short-term efficacy and long-term safety, Amantadine, 77 167–168 Armodafinil sleep induction and maintenance, 168–169 chemical structure, 212 Chronic obstructive sleep apnea multiple sclerosis, 222 (OSA), 178–179 narcolepsy, 218 Chronic primary insomnia obstructive sleep apnea, 219–221 adverse effects, 165, 167 pharmacokinetics, 214 comorbid psychiatric disorders, 164 R enantiomer, 213 double-blind trial, 164 safety, 224–225 efficacy, 165 shift work disorder, 223 long-term trial, 165 open-label extension phase, 165 post hoc analysis, 165–166 B psychomotor performance, 164–165 Benzodiazepine Withdrawal Symptom rebound insomnia, 164 Questionnaire (BWSQ), 183 WASO, 164–165 © Springer International Publishing Switzerland 2015 289 A. Guglietta (ed.), Drug Treatment of Sleep Disorders, Milestones -
Α4βδ GABAA Receptors Are High-Affinity Targets for Γ
α4βδ GABAA receptors are high-affinity targets for γ-hydroxybutyric acid (GHB) Nathan Absaloma,1, Laura F. Eghornb,1, Inge S. Villumsenb, Nasiara Karima, Tina Bayb, Jesper V. Olsenc, Gitte M. Knudsend, Hans Bräuner-Osborneb, Bente Frølundb, Rasmus P. Clausenb, Mary Chebiba,2, and Petrine Wellendorphb,2 aFaculty of Pharmacy A15, University of Sydney, Sydney, New South Wales 2006, Australia; bDepartment of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark; cNovo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; and dNeurobiology Research Unit and Center for Integrated Molecular Brain Imaging (Cimbi), Rigshospitalet and University of Copenhagen, 2100 Copenhagen, Denmark Edited by Leslie Lars Iversen, University of Oxford, Oxford, United Kingdom, and approved June 6, 2012 (received for review March 13, 2012) γ-Hydroxybutyric acid (GHB) binding to brain-specific high-affinity BnOPh-GHB) (8). Furthermore, several reports point to GHB- sites is well-established and proposed to explain both physiolog- induced effects that cannot be consequences of GABAB receptor ical and pharmacological actions. However, the mechanistic links activation alone: Fos expression studies with GHB indicate between these lines of data are unknown. To identify molecular a unique pattern of neuronal activation, which in several ways, is fi fi targets for speci c GHB high-af nity binding, we undertook pho- different from the pattern produced by the GABAB receptor tolinking studies combined with proteomic analyses and identified agonist baclofen (9). Numerous effects induced by GHB, including several GABAA receptor subunits as possible candidates. -
Phasic, Suprathreshold Excitation and Sustained Inhibition Underlie Neuronal Selectivity for Short-Duration Sounds
Phasic, suprathreshold excitation and sustained PNAS PLUS inhibition underlie neuronal selectivity for short-duration sounds Rishi K. Alluria, Gary J. Rosea,1, Jessica L. Hansona, Christopher J. Learyb, Gustavo A. Vasquez-Opazoa, Jalina A. Grahamc, and Jeremy Wilkersond aDepartment of Biology, University of Utah, Salt Lake City, UT 84112; bDepartment of Biology, University of Mississippi, Oxford, MS 38677; cNeuroscience Program, University of California, Davis, CA 95616; and dTalkingApe.org, Redwood City, CA 94063 Edited by Eric I. Knudsen, Stanford University School of Medicine, Stanford, CA, and approved January 29, 2016 (received for review October 23, 2015) Sound duration is important in acoustic communication, including experiments (18), suggested that sustained inhibition might be speech recognition in humans. Although duration-selective auditory critical for generating duration tuning. Whole-cell patch record- neurons have been found, the underlying mechanisms are unclear. ings in bats (19, 20) provided direct evidence that interplay be- To investigate these mechanisms we combined in vivo whole-cell tween excitation and inhibition contributed to duration selectivity. patch recordings from midbrain neurons, extraction of excitatory This work inspired a second type of coincidence model of duration and inhibitory conductances, and focal pharmacological manipula- selectivity (Fig. 1B) in which delayed, subthreshold excitation tions. We show that selectivity for short-duration stimuli results maximally summates with rebound from short-latency inhibition from integration of short-latency, sustained inhibition with delayed, (and/or offset excitation) over a narrow range of durations. Al- phasic excitation; active membrane properties appeared to amplify ternatively, Fuzessery and Hall (21) proposed an anticoincidence responses to effective stimuli. Blocking GABA receptors attenuated A model (Fig. -
At the Gabaa Receptor
THE EFFECTS OF CHRONIC ETHANOL INTAKE ON THE ALLOSTERIC INTERACTION BE T WEEN GABA AND BENZODIAZEPINE AT THE GABAA RECEPTOR THESIS Presented to the Graduate Council of the University of North Texas in Partial Fulfillment of the Requirements For the Degree of MASTER OF SCIENCE By Jianping Chen, B.S., M.S. Denton, Texas May, 1992 Chen, Jianping, The Effects of Chronic Ethanol Intake on the Allsteric Interaction Between GABA and BenzodiazeDine at the GABAA Receptor. Master of Science (Biomedical Sciences/Pharmacology), May, 1992, 133 pp., 4 tables, 3.0 figures, references, 103 titles. This study examined the effects of chronic ethanol intake on the density, affinity, and allosteric modulation of rat brain GABAA receptor subtypes. In the presence of GABA, the apparent affinity for the benzodiazepine agonist flunitrazepam was increased and for the inverse agonist R015-4513 was decreased. No alteration in the capacity of GABA to modulate flunitrazepam and R015-4513 binding was observed in membranes prepared from cortex, hippocampus or cerebellum following chronic ethanol intake or withdrawal. The results also demonstrate two different binding sites for [3H]RO 15-4513 in rat cerebellum that differ in their affinities for diazepam. Chronic ethanol treatment and withdrawal did not significantly change the apparent affinity or density of these two receptor subtypes. ACKNOWLEDGEMENT I would like to express my sincere thanks to my major professor, Dr. Michael W. Martin. .I deeply appreciate his guidance and direction which initiated this study, and his kindness in sharing his laboratory facilities with me. His suggestions, patience, encouragement and support in the laboratory have contributed significantly to my understanding of the receptor mechanism of drug action.