IUPHAR/BPS Guide to Pharmacology CITE
https://doi.org/10.2218/gtopdb/F72/2019.4

GABAA receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database



Delia Belelli1, Tim G. Hales1, Jeremy J. Lambert1, Bernhard Luscher2, Richard Olsen3, John A. Peters1, Uwe Rudolph4 and Werner Sieghart5
  1. University of Dundee, UK
  2. Pennsylvania State University, USA
  3. University of California Los Angels, USA
  4. Harvard Medical School, USA
  5. Medical University Vienna, Austria


Abstract

The GABAA receptor is a ligand-gated ion channel of the Cys-loop family that includes the nicotinic acetylcholine, 5-HT3 and strychnine-sensitive glycine receptors. GABAA receptor-mediated inhibition within the CNS occurs by fast synaptic transmission, sustained tonic inhibition and temporally intermediate events that have been termed ‘GABAA, slow’ [41]. GABAA receptors exist as pentamers of 4TM subunits that form an intrinsic anion selective channel. Sequences of six α, three β, three γ, one δ, three ρ, one ε, one π and one θ GABAA receptor subunits have been reported in mammals [273, 232, 231, 278]. The π-subunit is restricted to reproductive tissue. Alternatively spliced versions of many subunits exist (e.g. α4- and α6- (both not functional) α5-, β2-, β3- and γ2), along with RNA editing of the α3 subunit [67]. The three ρ-subunits, (ρ1-3) function as either homo- or hetero-oligomeric assemblies [354, 46]. Receptors formed from ρ-subunits, because of their distinctive pharmacology that includes insensitivity to bicuculline, benzodiazepines and barbiturates, have sometimes been termed GABAC receptors [354], but they are classified as GABAA receptors by NC-IUPHAR on the basis of structural and functional criteria [14, 232, 231].

Many GABAA receptor subtypes contain α-, β- and γ-subunits with the likely stoichiometry 2α.2β.1γ [164, 232]. It is thought that the majority of GABAA receptors harbour a single type of α- and β -subunit variant. The α1β2γ2 hetero-oligomer constitutes the largest population of GABAA receptors in the CNS, followed by the α2β3γ2 and α3β3γ2 isoforms. Receptors that incorporate the α4- α5-or α6-subunit, or the β1-, γ1-, γ3-, δ-, ε- and θ-subunits, are less numerous, but they may nonetheless serve important functions. For example, extrasynaptically located receptors that contain α6- and δ-subunits in cerebellar granule cells, or an α4- and δ-subunit in dentate gyrus granule cells and thalamic neurones, mediate a tonic current that is important for neuronal excitability in response to ambient concentrations of GABA [205, 268, 79, 17, 283]. GABA binding occurs at the β+/α- subunit interface and the homologous γ+/α- subunits interface creates the benzodiazepine site. A second site for benzodiazepine binding has recently been postulated to occur at the α+/β- interface ([250]; reviewed by [277]). The particular α-and γ-subunit isoforms exhibit marked effects on recognition and/or efficacy at the benzodiazepine site. Thus, receptors incorporating either α4- or α6-subunits are not recognised by ‘classical’ benzodiazepines, such as flunitrazepam (but see [351]). The trafficking, cell surface expression, internalisation and function of GABAA receptors and their subunits are discussed in detail in several recent reviews [48, 136, 184, 311] but one point worthy of note is that receptors incorporating the γ2 subunit (except when associated with α5) cluster at the postsynaptic membrane (but may distribute dynamically between synaptic and extrasynaptic locations), whereas as those incorporating the d subunit appear to be exclusively extrasynaptic.

NC-IUPHAR [14, 232] class the GABAA receptors according to their subunit structure, pharmacology and receptor function. Currently, eleven native GABAA receptors are classed as conclusively identified (i.e., α1β2γ2, α1βγ2, α3βγ2, α4βγ2, α4β2δ, α4β3δ, α5βγ2, α6βγ2, α6β2δ, α6β3δ and ρ) with further receptor isoforms occurring with high probability, or only tentatively [232, 231]. It is beyond the scope of this Guide to discuss the pharmacology of individual GABAA receptor isoforms in detail; such information can be gleaned in the reviews [14, 91, 164, 169, 140, 273, 212, 232, 231] and [8, 7]. Agents that discriminate between α-subunit isoforms are noted in the table and additional agents that demonstrate selectivity between receptor isoforms, for example via β-subunit selectivity, are indicated in the text below. The distinctive agonist and antagonist pharmacology of ρ receptors is summarised in the table and additional aspects are reviewed in [354, 46, 141, 219].

Several high-resolution cryo-electron microscopy structures have been described in which the full-length human α1β3γ2L GABAA receptor in lipid nanodiscs is bound to the channel-blocker picrotoxin, the competitive antagonist bicuculline, the agonist GABA (γ-aminobutyric acid), and the classical benzodiazepines alprazolam and diazepam [194].

Contents

This is a citation summary for GABAA receptors in the Guide to Pharmacology database (GtoPdb). It exists purely as an adjunct to the database to facilitate the recognition of citations to and from the database by citation analyzers. Readers will almost certainly want to visit the relevant sections of the database which are given here under database links.

GtoPdb is an expert-driven guide to pharmacological targets and the substances that act on them. GtoPdb is a reference work which is most usefully represented as an on-line database. As in any publication this work should be appropriately cited, and the papers it cites should also be recognized. This document provides a citation for the relevant parts of the database, and also provides a reference list for the research cited by those parts.

Please note that the database version for the citations given in GtoPdb are to the most recent preceding version in which the family or its subfamilies and targets were substantially changed. The links below are to the current version. If you need to consult the cited version, rather than the most recent version, please contact the GtoPdb curators.

Database links

GABAA receptors
http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=72
Introduction to GABAA receptors
http://www.guidetopharmacology.org/GRAC/FamilyIntroductionForward?familyId=72
    Channels and Subunits
            GABAA receptor α1 subunit
            http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=404
            GABAA receptor α2 subunit
            http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=405
            GABAA receptor α3 subunit
            http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=406
            GABAA receptor α4 subunit
            http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=407
            GABAA receptor α5 subunit
            http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=408
            GABAA receptor α6 subunit
            http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=409
            GABAA receptor β1 subunit
            http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=410
            GABAA receptor β2 subunit
            http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=411
            GABAA receptor β3 subunit
            http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=412
            GABAA receptor γ1 subunit
            http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=413
            GABAA receptor γ2 subunit
            http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=414
            GABAA receptor γ3 subunit
            http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=415
            GABAA receptor δ subunit
            http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=416
            GABAA receptor ε subunit
            http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=417
            GABAA receptor θ subunit
            http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=418
            GABAA receptor π subunit
            http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=419
            GABAA receptor ρ1 subunit
            http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=420
            GABAA receptor ρ2 subunit
            http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=421
            GABAA receptor ρ3 subunit
            http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=422

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