A Summary of Mechanistic Hypotheses of Gabapentin Pharmacology
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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. -
Inhibitory Role for GABA in Autoimmune Inflammation
Inhibitory role for GABA in autoimmune inflammation Roopa Bhata,1, Robert Axtella, Ananya Mitrab, Melissa Mirandaa, Christopher Locka, Richard W. Tsienb, and Lawrence Steinmana aDepartment of Neurology and Neurological Sciences and bDepartment of Molecular and Cellular Physiology, Beckman Center for Molecular Medicine, Stanford University, Stanford, CA 94305 Contributed by Richard W. Tsien, December 31, 2009 (sent for review November 30, 2009) GABA, the principal inhibitory neurotransmitter in the adult brain, serum (13). Because actions of exogenous GABA on inflammation has a parallel inhibitory role in the immune system. We demon- and of endogenous GABA on phasic synaptic inhibition both strate that immune cells synthesize GABA and have the machinery occur at millimolar concentrations (5, 8, 9), we hypothesized that for GABA catabolism. Antigen-presenting cells (APCs) express local mechanisms may also operate in the peripheral immune functional GABA receptors and respond electrophysiologically to system to enhance GABA levels near the inflammatory focus. We GABA. Thus, the immune system harbors all of the necessary first asked whether immune cells have synthetic machinery to constituents for GABA signaling, and GABA itself may function as produce GABA by Western blotting for GAD, the principal syn- a paracrine or autocrine factor. These observations led us to ask thetic enzyme. We found significant amounts of a 65-kDa subtype fl further whether manipulation of the GABA pathway in uences an of GAD (GAD-65) in dendritic cells (DCs) and lower levels in animal model of multiple sclerosis, experimental autoimmune macrophages (Fig. 1A). GAD-65 increased when these cells were encephalomyelitis (EAE). Increasing GABAergic activity amelio- stimulated (Fig. -
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 -
Structural Elements Required for Coupling Ion and Substrate Transport in the Neurotransmitter Transporter Homolog Leut
bioRxiv preprint doi: https://doi.org/10.1101/283176; this version posted July 6, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Classification: Biological Sciences, Biochemistry Title: Structural elements required for coupling ion and substrate transport in the neurotransmitter transporter homolog LeuT. Authors: Yuan-Wei Zhang1,3, Sotiria Tavoulari1,4, Steffen Sinning1, Antoniya A. Aleksandrova2, Lucy R. Forrest2 and Gary Rudnick1 Institutions: 1Department of Pharmacology, Yale School of Medicine, 333 Cedar Street, New Haven, CT 06520-8066; 2Computational Structural Biology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, 35A Convent Drive, Bethesda, MD 20892; 3School of Life Sciences, Guangzhou University, 230 Outer Ring West Rd., Higher Education Mega Center, Guangzhou, China 510006.4Current Address: Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Wellcome Trust/MRC Building, Cambridge Biomedical Campus, Hills Road, Cambridge, CB2 0XY United Kingdom. Corresponding Author: Gary Rudnick, Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520-8066, Tel: (203) 785-4548, Email: [email protected] bioRxiv preprint doi: https://doi.org/10.1101/283176; this version posted July 6, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. -
No Evidence of Altered in Vivobenzodiazepine Receptor Binding in Schizophrenia
No Evidence of Altered In Vivo Benzodiazepine Receptor Binding in Schizophrenia Anissa Abi-Dargham, M.D., Marc Laruelle, M.D., John Krystal, M.D., Cyril D’Souza, M.D., Sami Zoghbi, Ph.D., Ronald M. Baldwin, Ph.D., John Seibyl, M.D., Osama Mawlawi, Ph.D., Gabriel de Erasquin, M.D., Ph.D., Dennis Charney, M.D., and Robert B. Innis, M.D., Ph.D. Deficits in gamma-amino-butyric acid (GABA) of this measurement was established in four healthy neurotransmitter systems have been implicated in the volunteers. No differences in regional BDZ VT were pathophysiology of schizophrenia for more than two observed between 16 male schizophrenic patients and 16 decades. Previous postmortem and in vivo studies of matched controls. No relationships were observed between benzodiazepine (BDZ) receptor density have reported BDZ VT and severity of psychotic symptoms in any of the alterations in several brain regions of schizophrenic regions examined. In conclusion, this study failed to patients. The goal of this study was to better characterize identify alterations of BDZ receptors density in possible alterations of the in vivo regional distribution schizophrenia. If this illness is associated with deficits in volume (VT) of BDZ receptors in schizophrenia, using the GABA transmission, these deficits do not substantially selective BDZ antagonist [123I]iomazenil and single photon involve BDZ receptor expression or regulation. emission computerized tomography (SPECT). Regional [Neuropsychopharmacology 20:650-661, 1999] BDZ VT was measured under sustained radiotracer © 1999 American College of Neuropsychopharmacology. equilibrium conditions. The reproducibility and reliability Published by Elsevier Science Inc. KEY WORDS: Schizophrenia; Benzodiazepine receptors; that disinhibition of dopamine function in schizophre- [123I]iomazenil; SPECT nia may stem from a deficit in inhibitory, GABA medi- ated systems (Roberts 1972; Stevens 1975; van Kammen Alterations of gamma-amino-butyric acid (GABA) sys- 1977). -
Transporters
Alexander, S. P. H., Kelly, E., Mathie, A., Peters, J. A., Veale, E. L., Armstrong, J. F., Faccenda, E., Harding, S. D., Pawson, A. J., Sharman, J. L., Southan, C., Davies, J. A., & CGTP Collaborators (2019). The Concise Guide to Pharmacology 2019/20: Transporters. British Journal of Pharmacology, 176(S1), S397-S493. https://doi.org/10.1111/bph.14753 Publisher's PDF, also known as Version of record License (if available): CC BY Link to published version (if available): 10.1111/bph.14753 Link to publication record in Explore Bristol Research PDF-document This is the final published version of the article (version of record). It first appeared online via Wiley at https://bpspubs.onlinelibrary.wiley.com/doi/full/10.1111/bph.14753. Please refer to any applicable terms of use of the publisher. University of Bristol - Explore Bristol Research General rights This document is made available in accordance with publisher policies. Please cite only the published version using the reference above. Full terms of use are available: http://www.bristol.ac.uk/red/research-policy/pure/user-guides/ebr-terms/ S.P.H. Alexander et al. The Concise Guide to PHARMACOLOGY 2019/20: Transporters. British Journal of Pharmacology (2019) 176, S397–S493 THE CONCISE GUIDE TO PHARMACOLOGY 2019/20: Transporters Stephen PH Alexander1 , Eamonn Kelly2, Alistair Mathie3 ,JohnAPeters4 , Emma L Veale3 , Jane F Armstrong5 , Elena Faccenda5 ,SimonDHarding5 ,AdamJPawson5 , Joanna L Sharman5 , Christopher Southan5 , Jamie A Davies5 and CGTP Collaborators 1School of Life Sciences, -
Amino Acid Transporters As Tetraspanin TM4SF5 Binding Partners Jae Woo Jung1,Jieonkim2,Eunmikim2 and Jung Weon Lee 1,2
Jung et al. Experimental & Molecular Medicine (2020) 52:7–14 https://doi.org/10.1038/s12276-019-0363-7 Experimental & Molecular Medicine REVIEW ARTICLE Open Access Amino acid transporters as tetraspanin TM4SF5 binding partners Jae Woo Jung1,JiEonKim2,EunmiKim2 and Jung Weon Lee 1,2 Abstract Transmembrane 4 L6 family member 5 (TM4SF5) is a tetraspanin that has four transmembrane domains and can be N- glycosylated and palmitoylated. These posttranslational modifications of TM4SF5 enable homophilic or heterophilic binding to diverse membrane proteins and receptors, including growth factor receptors, integrins, and tetraspanins. As a member of the tetraspanin family, TM4SF5 promotes protein-protein complexes for the spatiotemporal regulation of the expression, stability, binding, and signaling activity of its binding partners. Chronic diseases such as liver diseases involve bidirectional communication between extracellular and intracellular spaces, resulting in immune-related metabolic effects during the development of pathological phenotypes. It has recently been shown that, during the development of fibrosis and cancer, TM4SF5 forms protein-protein complexes with amino acid transporters, which can lead to the regulation of cystine uptake from the extracellular space to the cytosol and arginine export from the lysosomal lumen to the cytosol. Furthermore, using proteomic analyses, we found that diverse amino acid transporters were precipitated with TM4SF5, although these binding partners need to be confirmed by other approaches and in functionally relevant studies. This review discusses the scope of the pathological relevance of TM4SF5 and its binding to certain amino acid transporters. 1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; Introduction on the plasma membrane and the mitochondria, lyso- Importing and exporting biological matter in and out of some, and other intracellular organelles. -
Alcohol and Violence: Neuropeptidergic Modulation of Monoamine Systems
Ann. N.Y. Acad. Sci. ISSN 0077-8923 ANNALS OF THE NEW YORK ACADEMY OF SCIENCES Issue: Addiction Reviews Alcohol and violence: neuropeptidergic modulation of monoamine systems Klaus A. Miczek,1,2 Joseph F. DeBold,2 Lara S. Hwa,2 Emily L. Newman,2 and Rosa M. M. de Almeida3 1Departments of Pharmacology, Psychiatry, and Neuroscience, Tufts University, Boston, Massachusetts. 2Department of Psychology, Tufts University, Medford, Massachusetts. 3Department of Psychology, LPNeC, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil Address for correspondence: Klaus A. Miczek, Department of Psychology, Tufts University, 530 Boston Ave (Bacon Hall), Medford, MA 02155. [email protected] Neurobiological processes underlying the epidemiologically established link between alcohol and several types of social, aggressive, and violent behavior remain poorly understood. Acute low doses of alcohol, as well as withdrawal from long-term alcohol use, may lead to escalated aggressive behavior in a subset of individuals. An urgent task will be to disentangle the host of interacting genetic and environmental risk factors in individuals who are predisposed to engage in escalated aggressive behavior. The modulation of 5-hydroxytryptamine impulse flow by gamma- aminobutyric acid (GABA) and glutamate, acting via distinct ionotropic and metabotropic receptor subtypes in the dorsal raphe nucleus during alcohol consumption, is of critical significance in the suppression and escalation of aggressive behavior. In anticipation and reaction to aggressive behavior, neuropeptides such as corticotropin- releasing factor, neuropeptide Y, opioid peptides, and vasopressin interact with monoamines, GABA, and glutamate to attenuate and amplify aggressive behavior in alcohol-consuming individuals. These neuromodulators represent novel molecular targets for intervention that await clinical validation. -
Functional Comparisons of Three Glutamate Transporter Subtypes Cloned from Human Motor Cortex
The Journal of Neuroscience, September 1994, 14(g): 5559-5569 Functional Comparisons of Three Glutamate Transporter Subtypes Cloned from Human Motor Cortex Jeffrey L. Arriza, Wendy A. Fairman, Jacques I. Wadiche, Geoffrey H. Murdoch, Michael P. Kavanaugh, and Susan G. Amara The Vellum Institute for Advanced Biomedical Research, Oregon Health Sciences University, Portland, Oregon 97201 Reuptake plays an important role in regulating synaptic and peripheral tissues(Christensen, 1990) and in the nervous system extracellular concentrations of glutamate. Three glutamate (Kanner and Schuldiner, 1987; Nicholls and Attwell, 1990). transporters expressed in human motor cortex, termed Transport serves a special function in the brain by mediating EAATl , EAATP, and EAAT3 (for excitatory amino acid trans- the reuptake of glutamate releasedat excitatory synapses.Glu- porter), have been characterized by their molecular cloning tamate can be reaccumulated from the synaptic cleft by the and functional expression. Each EAAT subtype mRNA was presynaptic nerve terminal (Eliasof and Werblin, 1993) or by found in all human brain regions analyzed. The most prom- glial uptake of transmitter diffusing from the cleft (Nicholls and inent regional variation in message content was in cerebel- Attwell, 1990; Schwartz and Tachibana, 1990; Barbour et al., lum where EAATl expression predominated. EAATl and 199 1). The activities of neuronal and glial transporters influence EAAT3 mRNAs were also expressed in various non-nervous the temporal and spatial dynamics of the chemical signal in tissues, whereas expression of EAATS was largely restricted other neurotransmitter systems(Hille, 1992; Bruns et al., 1993; to brain. The kinetic parameters and pharmacological char- Isaacsonet al., 1993), but such effects have not yet been dem- acteristics of transport mediated by each EAAT subtype onstrated at glutamatergic synapses(Hestrin et al., 1990; Sar- were determined in transfected mammalian cells by radio- antis et al., 1993). -
Tamás F. Freund
BK-SFN-NEUROSCIENCE_V11-200147-Freund.indd 50 6/19/20 2:08 PM Tamás F. Freund BORN: Zirc, Hungary June 14, 1959 EDUCATION: Loránd Eötvös University, Budapest, Hungary, Biologist (1983) Semmelweis University, Budapest and Hungarian Academy of Sciences, PhD (1986) APPOINTMENTS: Postdoctoral Fellow, Anatomy, Semmelweis University–Hungarian Academy of Sciences (1986–1990) Visiting Research Fellow, MRC Unit, Pharmacology, Oxford University (1986–1988) Head of Department, Institute of Experimental Medicine, Hungarian Academy of Sciences (IEM-HAS), Budapest (1990–1994) Professor, IEM-HAS, Deputy Director (1994–2002) and Director (2002–present) Professor and Head of Department, Péter Pázmány Catholic University, Budapest (2000–present) HONORS AND AWARDS (SELECTED): Drs. C. and F. Demuth Swiss Medical Research Foundation Award, Switzerland (1991) KRIEG Cortical Kudos Cortical Explorer Award of the Cajal Club (1991, USA) KRIEG Cortical Kudos Cortical Discoverer Award and the Cajal Medal (1998, USA) Dargut and Milena Kemali Foundation Award, FENS Forum, Berlin (1998) Fellow, Hungarian Academy of Sciences (1998), Vice President (since 2014) Bolyai Prize (2000), Széchenyi Prize, (2005), Prima Primissima Award (2013, Hungary) Fellow, Academia Europaea (2000, London) and Academia Scientiarum et Artium Europaea (2001) Fellow, German Academy of Sciences Leopoldina (2001) President, Federation of European Neuroscience Societies (FENS, 2004–2006) The Brain Prize (2011, Grete Lundbeck Foundation, Denmark) Fellow, American Academy of Arts and Sciences (2014) Doctor Honoris Causa, University of Southern Finland (2015) Tamás Freund’s main achievements include the discovery of new molecular pathways in nerve cell communication, identity and principles of neuron connectivity fundamental to cortical circuitry, and the generation of network activity patterns underlying multiple stages of information processing and storage in the brain. -
Diverse Small Molecules Prevent Macrophage Lysis During Pyroptosis Wendy P
Loomis et al. Cell Death and Disease (2019) 10:326 https://doi.org/10.1038/s41419-019-1559-4 Cell Death & Disease ARTICLE Open Access Diverse small molecules prevent macrophage lysis during pyroptosis Wendy P. Loomis1, Andreas B. den Hartigh1,BradT.Cookson1,2 and Susan L. Fink 1 Abstract Pyroptosis is a programmed process of proinflammatory cell death mediated by caspase-1-related proteases that cleave the pore-forming protein, gasdermin D, causing cell lysis and release of inflammatory intracellular contents. The amino acid glycine prevents pyroptotic lysis via unknown mechanisms, without affecting caspase-1 activation or pore formation. Pyroptosis plays a critical role in diverse inflammatory diseases, including sepsis. Septic lethality is prevented by glycine treatment, suggesting that glycine-mediated cytoprotection may provide therapeutic benefit. In this study, we systematically examined a panel of small molecules, structurally related to glycine, for their ability to prevent pyroptotic lysis. We found a requirement for the carboxyl group, and limited tolerance for larger amino groups and substitution of the hydrogen R group. Glycine is an agonist for the neuronal glycine receptor, which acts as a ligand- gated chloride channel. The array of cytoprotective small molecules we identified resembles that of known glycine receptor modulators. However, using genetically deficient Glrb mutant macrophages, we found that the glycine receptor is not required for pyroptotic cytoprotection. Furthermore, protection against pyroptotic lysis is independent of extracellular chloride conductance, arguing against an effect mediated by ligand-gated chloride channels. Finally, we conducted a small-scale, hypothesis-driven small-molecule screen and identified unexpected ion channel modulators that prevent pyroptotic lysis with increased potency compared to glycine. -
Amino Acid Transporters on the Guard of Cell Genome and Epigenome
cancers Review Amino Acid Transporters on the Guard of Cell Genome and Epigenome U˘gurKahya 1,2 , Ay¸seSedef Köseer 1,2,3,4 and Anna Dubrovska 1,2,3,4,5,* 1 OncoRay–National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden-Rossendorf, 01309 Dresden, Germany; [email protected] (U.K.); [email protected] (A.S.K.) 2 Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiooncology-OncoRay, 01328 Dresden, Germany 3 National Center for Tumor Diseases (NCT), Partner Site Dresden and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany 4 Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany 5 German Cancer Consortium (DKTK), Partner Site Dresden and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany * Correspondence: [email protected]; Tel.: +49-351-458-7150 Simple Summary: Amino acid transporters play a multifaceted role in tumor initiation, progression, and therapy resistance. They are critical to cover the high energetic and biosynthetic needs of fast- growing tumors associated with increased proliferation rates and nutrient-poor environments. Many amino acid transporters are highly expressed in tumors compared to the adjacent normal tissues, and their expression correlates with tumor progression, clinical outcome, and treatment resistance. Tumor growth is driven by epigenetic and metabolic reprogramming and is associated with excessive production of reactive oxygen species causing the damage of vital macromolecules, including DNA. This review describes the role of the amino acid transporters in maintaining tumor redox homeostasis, DNA integrity, and epigenetic landscape under stress conditions and discusses them as potential targets for tumor imaging and treatment.