DOCSLIB.ORG

Is There More to Gaba Than Synaptic Inhibition?

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Is There More to Gaba Than Synaptic Inhibition? REVIEWS IS THERE MORE TO GABA THAN SYNAPTIC INHIBITION? David F. Owens* and Arnold R. Kriegstein‡ In the mature brain, GABA (γ-aminobutyric acid) functions primarily as an inhibitory neurotransmitter. But it can also act as a trophic factor during nervous system development to influence events such as proliferation, migration, differentiation, synapse maturation and cell death. GABA mediates these processes by the activation of traditional ionotropic and metabotropic receptors, and probably by both synaptic and non-synaptic mechanisms. However, the functional properties of GABA receptor signalling in the immature brain are significantly different from, and in some ways opposite to, those found in the adult brain. The unique features of the early-appearing GABA signalling systems might help to explain how GABA acts as a developmental signal. The construction of the central nervous system (CNS) historical introduction to the establishment of GABA as results from a series of events that begins with neural a neurotransmitter substance, as well as an overview of induction and cellular proliferation, and ends with the components of the GABA signalling system. Then synapse formation and circuit refinement1. Each step in we discuss ontogenetic changes in GABA signalling the developmental sequence results from an interplay and potential developmental functions of GABA, between cell-intrinsic and cell-extrinsic signalling mech- focusing primarily on the mammalian neocortex, anisms2. Over the past half-century, many secreted mol- although other brain regions are also considered. ecules have been identified and shown to significantly influence individual developmental programmes. GABA as a neurotransmitter Neurotransmitters are a class of secreted molecules that The discovery of direct synaptic inhibition, with GABA might be important signals during nervous system devel- being the first clear example of an inhibitory neuro- opment. Although neurotransmitters are generally asso- transmitter substance, markedly altered views of synap- ciated with neuronal communication in the mature tic transmission, which had previously allowed for only *Laboratory of Molecular brain, multiple transmitter systems have been shown to excitatory signalling molecules10. GABA was first identi- Biology, National Institute of influence different aspects of neuronal maturation in fied in the mammalian brain over half a century Neurological Disorders and various experimental systems3–6. ago11,12. During the 1950s and 1960s, strong evidence Stroke, Building 36, Room 3C09, 36 Convent Drive, The amino acid GABA has long been considered accumulated that GABA was acting as an inhibitory Bethesda, Maryland 20892- to be the main inhibitory neurotransmitter in the neurotransmitter in both vertebrate and invertebrate 4092, USA. adult mammalian brain. However, GABA-mediated nervous systems13. For example, extracts from the ‡ Department of Neurology, signalling has also been implicated in the regulation mammalian brain contained a substance, termed fac- Columbia University College of Physicians & Surgeons, of nearly all the key developmental steps, from cell tor I, that blocked impulse generation in crayfish 630 West 168th Street, Box proliferation to circuit refinement. Considering that stretch receptor neurons14. Factor I was subsequently 31, New York, New York nearly all organisms, ranging from bacteria to shown to be GABA15. In crustaceans, GABA was found 10032, USA. humans, can synthesize GABA, it would be surprising to be approximately 100 times more concentrated in Correspondence to A.R.K. if multiple functions for GABA had not evolved7–9. inhibitory axons than in excitatory ones16,17, and in e-mail: [email protected] Here, we address the role of GABA-mediated signalling response to nerve stimulation, inhibitory nerve termi- doi:10.1038/nrn919 during brain development. We first provide a brief nals were found to secrete GABA18. Similar, although NATURE REVIEWS | NEUROSCIENCE VOLUME 3 | SEPTEMBER 2002 | 715 © 2002 Nature Publishing Group REVIEWS a less compelling, findings of GABA being concentrated Presynaptic Glia and released from inhibitory neurons were also made in the vertebrate brain19. The identification of biosyn- Glutamate thetic and metabolic pathways for GABA showed that the production, release, reuptake and metabolism of GAD GABAA Metabolism this substance occurred in the nervous system13.When GAT GABA was applied to nerve and muscle cells of both GABAB GABA vertebrates and invertebrates, it was generally found to GABA-T Ca2+ channel have inhibitory effects15,20–22 and to produce conduc- VGAT tance changes with ion sensitivities similar to those GABA observed after the activation of inhibitory nerves21,23–27. Finally, in the 1970s, GABA was localized to mam- malian nerve terminals28, and antibodies raised against GABA GABA-biosynthetic enzymes were shown to be A localized preferentially to known inhibitory neurons13. GABAB GAT K+ channel Postsynaptic The GABA neurotransmitter system FIGURE 1a provides a summary of the GABA neurotrans- b I mitter system. In the mammalian brain, GABA is syn- II thesized primarily from glutamate in a reaction that is catalysed by two glutamic acid decarboxylase (GAD) enzymes, GAD65 and GAD67 (REF.29). GABA is loaded III into synaptic vesicles by a vesicular neurotransmitter transporter (VGAT)30 and is liberated from nerve termi- nals by calcium-dependent exocytosis. However, non- IV vesicular forms of GABA secretion (for example, by reverse transporter action) have also been described and V might be particularly important during development31,32. The effects of GABA can be mediated by the activation of either IONOTROPIC or METABOTROPIC receptors, which can VI 100 µm be localized either pre- or postsynaptically. GABA sig- nals are terminated by reuptake of the neurotransmitter c into nerve terminals and/or into surrounding glial GABA GABA GABA A Cl– B C Cl– cells by a class of plasma-membrane GABA trans- porters (GATs)33; thereafter, GABA is metabolized by a transamination reaction that is catalysed by GABA transaminase (GABA-T)13. G G GABA neurons. There is a wide variety of GABA- producing neurons in the brain. In the neocortex, most Subunits: Subunits: Subunits: α1–6, β1–3, γ1–3, δ, R1a, R1b and R2 ρ1–3 GABA-containing neurons are local interneurons with ε, θ and π few, if any, dendritic spines, and are therefore classified as sparsely spiny, aspiny or smooth cells34–36. These cells are Figure 1 | Components of the GABA signalling pathway. a | Schematic diagram of the further classified into one of several basic groups, such as γ synthesis and transport of GABA ( -aminobutyric acid) at synapses. GABA is synthesized in basket cells, chandelier cells, double bouquet cells, local inhibitory neurons from glutamate by the enzyme glutamic acid decarboxylase (GAD), and is transported into vesicles by a vesicular neurotransmitter transporter (VGAT). GABA can be plexus neurons or neurogliaform cells (FIG. 1b). These released either vesicularly or non-vesicularly (by reverse transport). GABA receptors are located at subtypes differ in their morphology, neurochemical com- 35,37 pre- and postsynaptic sites. GABAB receptors are metabotropic receptors that cause presynaptic position, somatic location and terminal arborization . inhibition by suppressing calcium influx and reducing transmitter release, and achieve postsynaptic GABA-containing cells are distributed throughout the inhibition by activating potassium currents that hyperpolarize the cell. Reuptake of GABA by cortical lamina37–39. In addition, GABA interneurons can surrounding neurons and glia occurs through the activity of GABA transporters (GAT). be classified by intrinsic membrane properties and Subsequently, GABA is metabolized by a transamination reaction that is catalysed by GABA 40,41 transaminase (GABA-T). The metabolism of GABA occurs in both neurons (not shown) and glia. synaptic connectivity . Interestingly, experimental b | Cortical GABA interneurons are phenotypically diverse, as illustrated here by classification on data have indicated that most, if not all, neocortical the basis of morphological features. This figure illustrates (left to right) an interneuron with axonal GABA neurons are generated and migrate not from cor- arcades, a double bouquet cell, three types of basket cell, two chandelier cells, a cell spanning all tical, but rather from subcortical locations42.However, cortical layers and a neurogliaform cell. c | GABA receptors differ in subunit composition and this property might differ across species, as recent work assembly. GABA and GABA receptors are closely related pentameric receptors that carry A C in humans suggests that approximately 65% of neocorti- chloride; however, whereas GABAA receptors are composed of combinations of several subunit types, GABA receptors are composed of only single or multiple ρ-subunits. GABA receptors are cal GABA neurons arise from the neocortical prolifera- C B 43 metabotropic receptors that exist as R1a, R1b and R2 isoforms, and are associated with tive zone . Finally, in addition to local circuit neurons, direct GABA afferents project to the cortex from the G proteins. Native GABAB receptors are dimers composed of one R1 subunit and the R2 subunit. Modified, with permission, from REF.179 © 1987 The Institute of Mind and Behavior. basal forebrain and the ZONA INCERTA44–46. 716 | SEPTEMBER 2002 | VOLUME 3 www.nature.com/reviews/neuro © 2002 Nature Publishing Group REVIEWS GABA synapses. Initial electron-microscopic
Load more

Recommended publications
  • Molecular Mechanisms Driving Prostate Cancer Neuroendocrine Differentiation
    Molecular mechanisms driving prostate cancer neuroendocrine differentiation Submitted by Joseph Edward Sutton Supervisory team: Dr Amy Poole (DoS) Dr Jennifer Fraser Dr Gary Hutchison A thesis submitted in partial fulfilment of the requirements of Edinburgh Napier University, for the award of Doctor of Philosophy. October 2019 School of Applied Sciences Edinburgh Napier University Edinburgh Declaration It is hereby declared that this thesis is the result of the author’s original research. It has been composed by the author and has not been previously submitted for examination which has led to the award of a degree. Signed: II Dedication This thesis is dedicated to my grandfather William ‘Harry’ Russell, who died of stomach cancer in 2014. Thank you for always encouraging me to achieve my ambitions, believing in me and for retaining your incredible positivity and sense of humour, even at the very end of your life. III Acknowledgements First of all, I would like to acknowledge my parents, who dedicated so much effort and energy into helping me to achieve my lifelong ambition of becoming a scientist. From taking me to the Natural History and Science Museums in London as a child, to tolerating my obsession with Jurassic Park and continuing to support me in both of your unique yet equally important ways, thank you. I would also like to thank my PhD supervisors Dr Amy Poole and Dr Jenny Fraser, not only for their excellent scientific guidance but also for their great banter and encouragement along the way. Thank you for seeing some potential in me, taking a chance on me and for helping me to continue my scientific journey.
    [Show full text]
  • Design, Synthesis, and Evaluation of Novel Gram-Positive Antibiotics Part 2
    University of Wisconsin Milwaukee UWM Digital Commons Theses and Dissertations 12-1-2016 Part 1: Design, Synthesis, and Evaluation of Novel Gram-positive Antibiotics Part 2: Synthesis of Dihydrobenzofurans Via a New Transition Metal Catalyzed Reaction Part 3: Design, Synthesis, and Evaluation of Bz/gabaa Α6 Positive Allosteric Modulators Christopher Michael Witzigmann University of Wisconsin-Milwaukee Follow this and additional works at: https://dc.uwm.edu/etd Part of the Organic Chemistry Commons Recommended Citation Witzigmann, Christopher Michael, "Part 1: Design, Synthesis, and Evaluation of Novel Gram-positive Antibiotics Part 2: Synthesis of Dihydrobenzofurans Via a New Transition Metal Catalyzed Reaction Part 3: Design, Synthesis, and Evaluation of Bz/gabaa Α6 Positive Allosteric Modulators" (2016). Theses and Dissertations. 1429. https://dc.uwm.edu/etd/1429 This Dissertation is brought to you for free and open access by UWM Digital Commons. It has been accepted for inclusion in Theses and Dissertations by an authorized administrator of UWM Digital Commons. For more information, please contact [email protected]. PART 1: DESIGN, SYNTHESIS, AND EVALUATION OF NOVEL GRAM-POSITIVE ANTIBIOTICS PART 2: SYNTHESIS OF DIHYDROBENZOFURANS VIA A NEW TRANSITION METAL CATALYZED REACTION PART 3: DESIGN, SYNTHESIS, AND EVALUATION OF BZ/GABAA α6 POSITIVE ALLOSTERIC MODULATORS by Christopher Michael Witzigmann A Dissertation Submitted in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy in Chemistry at The University of Wisconsin-Milwaukee December 2016 ABSTRACT PART 1: DESIGN, SYNTHESIS, AND EVALUATION OF NOVEL GRAM-POSITIVE ANTIBIOTICS PART 2: SYNTHESIS OF DIHYDROBENZOFURANS VIA A NEW TRANSITION METAL CATALYZED REACTION PART 3: DESIGN, SYNTHESIS, AND EVALUATION OF BZ/GABAA α6 POSITIVE ALLOSTERIC MODULATORS by Christopher Michael Witzigmann The University of Wisconsin-Milwaukee, 2016 Under the Supervision of Distinguished Professor James M.
    [Show full text]
  • Molecular Biology of Insect Neuronal GABA Receptors Molecular Biology of Insect Neuronal GABA Receptors
    R EVIEW A.M. Hosie et al. – Molecular biology of insect neuronal GABA receptors Molecular biology of insect neuronal GABA receptors Alastair M. Hosie, Kate Aronstein, David B. Sattelle and Richard H. ffrench-Constant Ionotropic g-aminobutyric acid (GABA) receptors are distributed throughout the nervous systems of many insect species. As with their vertebrate counterparts, GABAA receptors and GABAC receptors, the binding of GABA to ionotropic insect receptors elicits a rapid, transient opening of anion-selective ion channels which is generally inhibitory.Although insect and vertebrate GABA receptors share a number of structural and functional similarities, their pharmacology differs in several aspects. Recent studies of cloned Drosophila melanogaster GABA receptors have clarified the contribution of particular subunits to these differences. Insect ionotropic GABA receptors are also the target of numerous insecticides and an insecticide-resistant form of a Drosophila GABA- receptor subunit has enhanced our understanding of the structure–function relationship of one aspect of pharmacology common to both insect and vertebrate GABA receptors, namely antagonism by the plant-derived toxin picrotoxinin. Trends Neurosci. (1997) 20, 578–583 ONOTROPIC RECEPTORS for the neurotransmitter nicotinic acetylcholine receptors (nAChRs), strychnine- Ig-aminobutyric acid (GABA) are widespread mediators sensitive glycine receptors and serotonin type-3 receptors of rapid neurotransmission in the nervous systems of (5-HT3 receptors) (Ref. 12). Such receptors are formed both vertebrates and invertebrates1,2. In these receptors by the oligomerization of five subunits around a central, the binding of GABA elicits the rapid gating of an inte- transmitter-gated ion channel. Although cys-loop recep- gral chloride-selective ion channel.
    [Show full text]
  • Distinct Ionotropic GABA Receptors Mediate Presynaptic and Postsynaptic Inhibition in Retinal Bipolar Cells
    The Journal of Neuroscience, April 1, 2000, 20(7):2673–2682 Distinct Ionotropic GABA Receptors Mediate Presynaptic and Postsynaptic Inhibition in Retinal Bipolar Cells Colleen R. Shields,1,3 My N. Tran,1 Rachel O. L. Wong,2,3 and Peter D. Lukasiewicz1,2,3 1Department of Ophthalmology and Visual Sciences, 2Department of Anatomy and Neurobiology, and 3Neuroscience Program, Washington University School of Medicine, St. Louis, Missouri 63110 Ionotropic GABA receptors can mediate presynaptic and postsyn- immunoreactivity was intense in the outer and inner plexiform ␳ aptic inhibition. We assessed the contributions of GABAA and layers (OPL and IPL, respectively). GABAC subunit labeling GABAC receptors to inhibition at the dendrites and axon terminals was weak in the OPL but strong in the IPL in which puncta of ferret retinal bipolar cells by recording currents evoked by focal colocalized with terminals of rod bipolars immunoreactive for application of GABA in the retinal slice. Currents elicited at the protein kinase C and of cone bipolars immunoreactive for dendrites were mediated predominantly by GABAA receptors, calbindin or recoverin. These data demonstrate that GABAA whereas responses evoked at the terminals had GABAA and receptors mediate GABAergic inhibition on bipolar cell den- GABAC components. The ratio of GABAC to GABAA (GABAC: drites in the OPL, that GABAA and GABAC receptors mediate GABAA) was highest in rod bipolar cell terminals and variable inhibition on axon terminals in the IPL, and that the GABAC: among cone bipolars, but generally was lower in OFF than in GABAA on the terminals may tune the response characteristics ON classes. Our results also suggest that the GABAC:GABAA of the bipolar cell.
    [Show full text]
  • Methoxy-6-Methylflavone and Kavain at Recombinant GABAA Receptors
    Pharmacology profile of 2′-methoxy-6-methylflavone and kavain at recombinant GABAA receptors Han Chow Chua BPharm (Hons) A thesis submitted in fulfilment of the requirements for the award of Doctor of Philosophy Faculty of Pharmacy The University of Sydney 2016 Acknowledgements Firstly, I would like to express my sincere gratitude to my supervisor Professor Mary Collins for her continuous support, guidance, patience and motivation throughout my PhD. Besides my supervisor, I would like to thank Professor Jane Hanrahan, Dr Nathan Absalom and Dr Petra van Nieuwenhuijzen for their insightful comments and encouragement, which were precious for the writing of this thesis. My sincere appreciation also goes to Associate Professor Philip Ahring for providing me with valuable guidance in molecular biology and electrophysiology; Associate Professor Thomas Balle for his immense knowledge in molecular modelling; Dr Raja Viswas for the synthesis of various chemicals used in this study. I would also like to thank my colleagues and lab buddies (in no particular order): Vivian, Irene, Radhika, Zirong, Taima, Leonny, Jia, Bryan, Ting, Steve, Terry, Tim, Izumi, Ida and Maja for their friendship, support, shared knowledge and experiences over the years, which helped me stay sane through those hair-pulling moments. Last but not least, my heartfelt gratitude goes to my family, as none of this would have been possible without their support. They have been a constant source of love, concern, support and strength throughout all these years and I deeply appreciate their faith in me. Abstract GABAA receptors (GABAARs) are a class of physiologically- and therapeutically- important ligand-gated ion channels.
    [Show full text]
  • Dysregulated Expression of Neuregulin-1 by Cortical Pyramidal Neurons Disrupts Synaptic Plasticity
    Cell Reports Article Dysregulated Expression of Neuregulin-1 by Cortical Pyramidal Neurons Disrupts Synaptic Plasticity Amit Agarwal,1,7,8 Mingyue Zhang,2,8 Irina Trembak-Duff,2,8 Tilmann Unterbarnscheidt,1,8 Konstantin Radyushkin,3,9 Payam Dibaj,1 Daniel Martins de Souza,4,10 Susann Boretius,5 Magdalena M. Brzo´ zka,1,11 Heinz Steffens,6 Sebastian Berning,6 Zenghui Teng,2 Maike N. Gummert,1 Martesa Tantra,3 Peter C. Guest,4 Katrin I. Willig,6 Jens Frahm,5 Stefan W. Hell,6 Sabine Bahn,4 Moritz J. Rossner,1,11 Klaus-Armin Nave,1 Hannelore Ehrenreich,3 Weiqi Zhang,2,* and Markus H. Schwab1,12,* 1Department of Neurogenetics, Max Planck Institute of Experimental Medicine, 37075 Go¨ ttingen, Germany 2Laboratory of Molecular Psychiatry, Department of Psychiatry, University of Mu¨ nster, 48149 Muenster Germany 3Clinical Neuroscience, Max Planck Institute of Experimental Medicine, 37075 Go¨ ttingen, Germany 4Institute of Biotechnology, University of Cambridge, Cambridge CB2 1QT, UK 5Biomedizinische NMR Forschungs GmbH, Max Planck Institute of Biophysical Chemistry, 37077 Go¨ ttingen, Germany 6Department of NanoBiophotonics, Max Planck Institute for Biophysical Chemistry, 37077 Go¨ ttingen, Germany 7Solomon H. Snyder Department of Neuroscience, Johns Hopkins University, Baltimore, MD 21025, USA 8Co-first author 9Present address: Department of Physiological Chemistry, Focus Program Translational Neurosciences, Johannes Gutenberg University of Mainz, 55131 Mainz, Germany 10Present address: Laboratory of Neuroproteomics, Department of Biochemistry, Institute of Biology, State University of Campinas (UNICAMP), Campinas, Sao Paulo 13083-970, Brazil 11Present address: Department of Psychiatry, Ludwig-Maximilian-University Munich, 81377 Munich, Germany 12Present address: Cellular Neurophysiology, Hannover Medical School, 30625 Hannover, Germany *Correspondence: [email protected] (W.Z.), [email protected] (M.H.S.) http://dx.doi.org/10.1016/j.celrep.2014.07.026 This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).
    [Show full text]
  • Molecular Characterization of GABA-A Receptor Subunit Diversity Within Major Peripheral Organs and Their Plasticity in Response to Early Life Psychosocial Stress
    fnmol-11-00018 February 3, 2018 Time: 13:27 # 1 ORIGINAL RESEARCH published: 06 February 2018 doi: 10.3389/fnmol.2018.00018 Molecular Characterization of GABA-A Receptor Subunit Diversity within Major Peripheral Organs and Their Plasticity in Response to Early Life Psychosocial Stress Ethan A. Everington†, Adina G. Gibbard†, Jerome D. Swinny* and Mohsen Seifi* Institute for Biomedical and Biomolecular Sciences and School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth, United Kingdom Gamma aminobutyric acid (GABA) subtype A receptors (GABAARs) are integral membrane ion channels composed of five individual proteins or subunits. Up to 19 different GABAAR subunits (a1–6, b1–3, g1–3, d, +, ", p, and r1–3) have been identified, resulting in anatomically, physiologically, and pharmacologically distinct multiple receptor Edited by: subtypes, and therefore GABA-mediated inhibition, across the central nervous system Gregg E. Homanics, (CNS). Additionally, GABAAR-modulating drugs are important tools in clinical medicine, University of Pittsburgh, United States although their use is limited by adverse effects. While significant advances have been Reviewed by: Hartmut Lüddens, made in terms of characterizing the GABAAR system within the brain, relatively less Johannes Gutenberg-Universität is known about the molecular phenotypes within the peripheral nervous system of Mainz, Germany major organ systems. This represents a potentially missed therapeutic opportunity Tija Jacob, University of Pittsburgh, United States in terms of utilizing or repurposing clinically available GABAAR drugs, as well as *Correspondence: promising research compounds discarded due to their poor CNS penetrance, for Jerome D. Swinny the treatment of peripheral disorders. In addition, a broader understanding of the [email protected] Mohsen Seifi peripheral GABAAR subtype repertoires will contribute to the design of therapies mohsen.seifi@port.ac.uk which minimize peripheral side-effects when treating CNS disorders.
    [Show full text]
  • UC San Francisco Electronic Theses and Dissertations
    UCSF UC San Francisco Electronic Theses and Dissertations Title Candidate Gene Analysis of Panic Disorder Permalink https://escholarship.org/uc/item/5gt4f0p4 Author Hodges, Laura Michelle Publication Date 2008-06-16 Peer reviewed|Thesis/dissertation eScholarship.org Powered by the California Digital Library University of California Candidate Gene Analysis of Panic Disorder by Laura M. Hodges DISSERTATION Submitted in partial satisfaction of the requirements for the degree of DOCTOR OF PHILOSOPHY in Pharmaceutical Sciences and Pharmacogenomics in the GRADUATE DIVISION of the UNIVERSITY OF CALIFORNIA, SAN FRANCISCO Copyright 2008 by Laura M. Hodges ii Acknowledgements Principal investigator: Steve Hamilton Laboratory contributors: Oscar Bravo, Maria Bautista Oral and thesis committee chair: Laura Bull Oral committee members: Dave Glidden, Pui Kwok, Xin Chen Thesis committee members: Laura Bull, Esteban Burchard Collaborators and sample contributors: Myrna Weissman, Abby Fyer Statistical contributors: Ramiro Costa, Oleg Evgrafov, Fatemeh Haghighi Publication: Hodges LM, et al. Association and linkage analysis of candidate genes GRP, GRPR, CRHR1, and TACR1 in panic disorder. Am J Med Genet B Neuropsychiatr Genet. 2008 May 1. (Epub ahead of print)_PMID: 18452185. The material in this publication has been granted permission for reprint in this dissertation by Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc. iii Abstract Candidate Gene Analysis of Panic Disorder Laura M. Hodges Panic disorder (PD) is a common anxiety disorder of unknown etiology, with a modest contribution estimated to come from multiple genes. Although pharmacological and behavioral remedies are helpful, PD carries a significant personal and socioecomonic burden in the population. Evidence from basic and pharmaceutical research implicates a number of genes in PD.
    [Show full text]
  • Expression of Gamma-Aminobutyric Acid Receptors on Neoplastic Growth
    Zhang et al. Journal of Translational Medicine 2013, 11:102 http://www.translational-medicine.com/content/11/1/102 RESEARCH Open Access Expression of gamma-aminobutyric acid receptors on neoplastic growth and prediction of prognosis in non-small cell lung cancer Xiaoxue Zhang1,2, Rong Zhang2, Yuanjie Zheng2, Jianfei Shen2, Dakai Xiao2, Jin Li2, Xiaoshun Shi2, Liyan Huang2, Hailing Tang2, Jun Liu2, Jianxing He2* and Haibo Zhang2,3 Abstract Background: Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the adult mammalian brain, but exerts physiologic effects other than that on neurotransmitter in non-neuronal peripheral tissues and organs. GABA may affect cancer growth through activation GABA receptors. We investigated the gene expression of GABA receptors in tissue of non-small cell lung cancers (NSCLC) and non-cancerous tissues, and found that the gene expression of GABA receptor phenotypes was correlated with tumorigenesis and clinical prognosis. Methods: Sixty-one snap-frozen human samples of NSCLC tissues and paired non-cancerous tissues (5cm away from tumor) were analyzed. Gene expression of GABA receptors was detected by Real-time quantitative PCR (RT-qPCR). Survival times in relation to the expression of GABA receptor phenotypes were analyzed. Human NSCLC cell lines H1299, A549, H520, H460 and human bronchial epithelial cell line BEAS-2B were used to determine the phenotypes of GABA inhibitory effects on cancer cell growth. The effects of exogenous administration of GABA on H1299 cell growth were examined. Results: The gene expressions were significantly higher in NSCLC tissues than in the paired non-cancerous tissues for GABAA receptor subunit α3(GABRA3, P =0.030);forGABAA receptor subunit epsilon (GABRE, P = 0.036); and GABAB receptor subunit 2 (GABBR2, P = 0.005).
    [Show full text]
  • Potentiation of the Response of GABAA Receptors by Bangladeshi
    S. TSUBAKI et al. Food Sci. Technol. Res., 15 (3), 315–324, 2009 References pretreatment of lignocellulosic biomass. Bioresour. Technol., 96, Adam, D. (2003). Out of the kitchen. Nature, 421, 571-572. 673-686. Potentiation of the Response of GABAA Receptors by Bangladeshi Medicinal Plants $NL\D16DYDJH3( 5ROHVRIZDWHUIRUFKHPLFDOUHDF- 2NXER.,LMLPD0.RED\DVKL<<RVKLNRVKL08FKLGD7 tions in high-temperature water. Chem. Rev., 102, 2725-2750. .XGRX6 &RPSRQHQWVUHVSRQVLEOHIRUWKHXQGHVLUDEOH 1 2 4 1 4 $]XPD-7DQDND).RVKLMLPD7 (QKDQFHPHQWRIHQ- taste of soybean seeds. Biosci. Biotech. Biochem., 56, 99-103. Sanzida MUBASSARA , Sheikh Julfikar HOSSAIN , Firoj AHMED , Makie YAMAMOTO , Nobusuke TAN and 1* ]\PDWLFVXVFHSWLELOLW\RIOLJQRFHOOXORVLFZDVWHVE\PLFURZDYH 2RNXVKL<6DNDPRWR0$]XPD- 2SWLPL]DWLRQRI Hitoshi AOSHIMA irradiation. J. Ferment. Technol., 62, 377-384. microwave-assisted extraction of polysaccharides from fruiting 'XERLV0*LOOHV.$+DPLOWRQ-.5HEHUV3$6PLWK) body of mushrooms. J Appl. Glycosci., 53, 267-272. 1 Applied Molecular Bioscience, Graduate School of Medicine, Yamaguchi University, 1677-1 Yoshida, Yamaguchi 753-8512, Japan &RORULPHWULFPHWKRGIRUGHWHUPLQDWLRQRIVXJDUVDQGUH- 2¶7RRO'. &KDUDFWHULVWLFVDQGXVHRIRNDUDWKHVR\EHDQ 2 Biotechnology and Genetic Engineering Discipline, Khulna University, Khulna-9208, Bangladesh lated substances. Anal. Chem., 28, 350-356. residue from soy milk production-a review. J. Agric. Food Chem., 3 Pharmacy Discipline, Khulna University, Khulna-9208, Bangladesh )ROLQ2'HQLV: $FRORULPHWULFPHWKRGIRUWKHGHWHU- 47, 363-371. 4 Exercise and Health Science, Faculty of Education, Yamaguchi University, 1677-1 Yoshida, Yamaguchi 753-8512, Japan mination of phenols (and phenol derivatives) in urine. J. Biol. 3DUHMR,3HWUDNLV&.HIDODV3 $WUDQVLWLRQPHWDOHQ- Chem., 22, 305-308. hanced luminol chemiluminescence in the presence of a chelator. Received October 23, 2008; Accepted February 26, 2009 .DUU/LOLHQWKDO/..DG]HUH&7*ULHVKRS&0)DKH\-U*& J.
    [Show full text]
  • Evidence for Inhibition Mediated by Coassembly of GABAA and GABAC Receptor Subunits in Native Central Neurons
    The Journal of Neuroscience, August 18, 2004 • 24(33):7241–7250 • 7241 Cellullar/Molecular Evidence for Inhibition Mediated by Coassembly of GABAA and GABAC Receptor Subunits in Native Central Neurons Carol J. Milligan,1* Noel J. Buckley,1,2 Maurice Garret,3 Jim Deuchars,1 and Susan A. Deuchars1* 1School of Biomedical Sciences, University of Leeds, Leeds LS2 9NQ, United Kingdom, 2School of Biochemistry and Molecular Biology, University of Leeds, Leeds, LS2 9JT, United Kingdom, and 3Laboratoire de Neurophysiologie, Centre National de la Recherche Scientifique, Unite´ Mixte de Recherche 5543, Universitie de Bordeaux I, Bordeaux, France ␣ ␤ ␥ Fast inhibition in the nervous system is commonly mediated by GABAA receptors comprised of 2 /2 /1 subunits. In contrast, GABAC receptors containing only ␳ subunits (␳1-␳3) have been predominantly detected in the retina. However, here using reverse transcription- PCR and in situ hybridization we show that mRNA encoding the ␳1 subunit is highly expressed in brainstem neurons. Immunohisto- chemistry localized the ␳1 subunit to neurons at light and electron microscopic levels, where it was detected at synaptic junctions. ␮ ␳ Application of the GABAC receptor agonist cis-4-aminocrotonic acid (100–800 M) requires the 1 subunit to elicit responses, which ␮ surprisingly are blocked independently by antagonists to GABAA (bicuculline, 10 M) and GABAC [(1,2,5,6-tetrahydropyridin-4- ␮ yl)methylphosphinic acid (TPMPA); 40–160 M] receptors. Responses to GABAC agonists were also enhanced by the GABAA receptor modulator pentobarbitone (300 ␮M). Spontaneous and evoked IPSPs were reduced in amplitude but never abolished by TPMPA, but were completely blocked by bicuculline. We therefore tested the hypothesis that GABAA and GABAC subunits formed a heteromeric receptor.
    [Show full text]
  • Syrian Hamsters As a Clinically Relevant Model
    SYRIAN HAMSTERS AS CLINICALLY RELEVANT MODELS FOR MOOD DISORDERS A Dissertation by JOHN LORENZ SHANNONHOUSE Submitted to the Office of Graduate and Professional Studies of Texas A&M University in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY Chair of Committee Michael Smotherman Committee Members Caurnel Morgan Shoshana Eitan Gerald Frye Head of Department Thomas McKnight May 2017 Major Subject: Neuroscience Copyright 2017 John Shannonhouse ABSTRACT Anxiety and depressive disorders are the two most common types of mood disorders in the United States. These disorders are more likely to affect women than men. Animal models do not cover key aspects of mood disorders well, including sex biases, links between metabolism, HPA activity, social status and anxiety and depression as well as paradoxical effects of antidepressants on some adolescents. It is reported here that two novel tests, the anxiety feeding/exploration conflict (AFEC) test and the reward/investigational preference (RIP) test, are suitable for measuring anxiety-like and depression-like behavior in Syrian hamsters (Mesocricetus auratus). Furthermore, biometrics including body weight, food intake, indirect calorimetry, plasma assays and tissue weights measured metabolism. Gene expression and electrophysiology were used to measure brain function. Ph.armacological interventions manipulated behavior and metabolism. Animals were manipulated through social housing (SH, 2 or more animals per cage) and social separation (SS, one animal per cage) and pharmacology to model mood disorders in humans. Relative to SH, SS hamsters show a combination of increased metabolic rate, hypophagia, decreased adiposity, decreased lean mass, low HPA activity and increased anxiety-like and depression-like behaviors with a profound female sex bias.
    [Show full text]