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      Structural insights into the interaction between gabazine (SR-95531) and Laodelphax striatellus GABA receptors

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          Abstract

          γ-Aminobutyric acid receptors (GABARs) mediate fast inhibitory neurotransmission and are targets for insecticides. GABARs are composed of five subunits, the composition of which dictates the pharmacological characteristics of GABARs. Both competitive and noncompetitive GABAR antagonists can be used as insecticides. Gabazine is a potent competitive antagonist of mammalian α1β2γ2 GABARs; however, it is less potent against insect GABARs. To explore how gabazine interacts with GABARs, we examined whether the sensitivity of the small brown planthopper ( Laodelphax striatellus) RDL GABAR (LsRDLR) to gabazine is increased when its amino acid residues are substituted with α1β2γ2 GABAR residues. In the results, two of the generated mutants showed enhanced gabazine sensitivity. Docking simulations of gabazine using LsRDLR homology models and an α1β2γ2 GABAR cryo-EM structure revealed that the accommodation of gabazine into the “aromatic box” in the orthosteric site lowered the binding energy. This information may help in designing GABAR-targeting insecticides with novel modes of action.

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          Variations on an inhibitory theme: phasic and tonic activation of GABA(A) receptors.

          Mark Farrant, Zoltan Nusser (2005)
          The proper functioning of the adult mammalian brain relies on the orchestrated regulation of neural activity by a diverse population of GABA (gamma-aminobutyric acid)-releasing neurons. Until recently, our appreciation of GABA-mediated inhibition focused predominantly on the GABA(A) (GABA type A) receptors located at synaptic contacts, which are activated in a transient or 'phasic' manner by GABA that is released from synaptic vesicles. However, there is growing evidence that low concentrations of ambient GABA can persistently activate certain subtypes of GABA(A) receptor, which are often remote from synapses, to generate a 'tonic' conductance. In this review, we consider the distinct roles of synaptic and extrasynaptic GABA receptor subtypes in the control of neuronal excitability.
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            Structure of a human synaptic GABA-A receptor

            Shaotong Zhu, Colleen Noviello, Jinfeng Teng … (2018)
            Fast inhibitory neurotransmission in the brain is principally mediated by the neurotransmitter γ-aminobutyric acid (GABA) and its synaptic target, the GABA-A receptor. Dysfunction of this receptor results in neurological disorders and mental illnesses including epilepsy, anxiety and insomnia. The GABA-A receptor is also a prolific target for therapeutic, illicit, and recreational drugs, including benzodiazepines, barbiturates, anesthetics and ethanol. We present high resolution cryo-electron microscopy structures of the human α1β2γ2 GABA-A receptor, the predominant isoform in the adult brain. The receptor is bound to GABA and the benzodiazepine site antagonist flumazenil, the first-line clinical treatment for benzodiazepine overdose. The receptor architecture reveals unique heteromeric interactions for this important class of inhibitory neurotransmitter receptors. This work provides a template for understanding receptor modulation by GABA and benzodiazepines, and will assist rational approaches to therapeutic targeting of this receptor for neurological disorders and mental illness.
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              GABA A receptor signalling mechanisms revealed by structural pharmacology

              Simonas Masiulis, Rooma Desai, Tomasz Uchański … (2019)
              Summary Type-A γ-aminobutyric receptors (GABAARs) are ligand-gated chloride channels with a very rich pharmacology. Some of their modulators, including benzodiazepines and general anaesthetics, are among the most successful drugs in clinical use and common substances of abuse. Without reliable structural data, the mechanistic basis for pharmacological modulation of GABAARs remains largely unknown. Here we report high-resolution cryoEM structures of the full-length human α1β3γ2L GABAAR in lipid nanodiscs, bound to the channel blocker picrotoxin, the competitive antagonist bicuculline, the agonist GABA and the classical benzodiazepines alprazolam (Xanax) and diazepam (Valium), respectively. We describe the binding modes and mechanistic impacts of these ligands, the closed and desensitised states of the GABAAR gating cycle, and the basis for allosteric coupling between the extracellular, agonist-binding, and the transmembrane, pore-forming, regions. This work provides a structural framework to integrate decades of physiology and pharmacology research and a rational basis for development of novel GABAAR modulators.
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                Author and article information

                Journal
                Journal ID (nlm-ta): J Pestic Sci
                Journal ID (iso-abbrev): J Pestic Sci
                Title: Journal of Pesticide Science
                Publisher: Pesticide Science Society of Japan (Nakazato 2-28-10, Kita-ku, Tokyo 114-0015, Japan )
                ISSN (Print): 1348-589X
                ISSN (Electronic): 1349-0923
                Publication date (Print): 20 May 2022
                Volume: 47
                Issue: 2
                Pages: 78-85
                Affiliations
                [1 ]Faculty of Life and Environmental Sciences, Shimane University, Matsue, Shimane 690–8504, Japan
                [2 ]Key Laboratory for Green Chemical Process of Ministry of Education, School of Chemical Engineering and Pharmacy, Wuhan Institute of Technology, Wuhan, Hubei 430205, People’s Republic of China
                [3 ]Interdisciplinary Institute for Science Research, Organization for Research and Academic Information, Shimane University, Matsue, Shimane 690–8504, Japan
                Author notes
                [*] [* ]To whom correspondence should be addressed. E-mail: liugenyan@ 123456wit.edu.cn , ozoe-y@ 123456life.shimane-u.ac.jp
                Article
                DOI: 10.1584/jpestics.D22-007
                PMC ID: 9184248
                PubMed ID: 35800394
                SO-VID: 838e0679-9cf2-42b5-9665-8e1fb2c9df47
                Copyright © © 2022 Pesticide Science Society of Japan
                License:

                This is an open access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) License.

                History
                Date received : 23 February 2022
                Date accepted : 13 April 2022
                Categories
                Subject: Regular Article

                Keywords: γ-aminobutyric acid,gaba receptor,insecticide,competitive antagonist,gabazine,small brown planthopper
                Data availability:
                Keywords: γ-aminobutyric acid, gaba receptor, insecticide, competitive antagonist, gabazine, small brown planthopper

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