The GABA_A receptor is a ligand-gated ion channel of the Cys-loop family that includes the nicotinic acetylcholine, 5-HT₃ and strychnine-sensitive glycine receptors. GABA_A receptor-mediated inhibition within the CNS occurs by fast synaptic transmission, sustained tonic inhibition and temporally intermediate events that have been termed 'GABA_A, slow' [12]. GABA_A 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 GABA_A receptor subunits have been reported in mammals [45-46,54,58]. 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 [15]. The three ρ-subunits, (ρ1-3) function as either homo- or hetero-oligomeric assemblies [13,71]. Receptors formed from ρ-subunits, because of their distinctive pharmacology that includes insensitivity to bicuculline, benzodiazepines and barbiturates, have sometimes been termed GABA_C receptors [71], but they are classified as GABA_A receptors by NC-IUPHAR on the basis of structural and functional criteria [6,45-46].

Many GABA_A receptor subtypes contain α-, β- and γ-subunits with the likely stoichiometry 2α.2β.1γ [33,45]. It is thought that the majority of GABA_A receptors harbour a single type of α- and β -subunit variant. The α1β2γ2 hetero-oligomer constitutes the largest population of GABA_A 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 [7,17,41,52,60]. 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 ([49]; reviewed by [57]). 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 [69]). The trafficking, cell surface expression, internalisation and function of GABA_A receptors and their subunits are discussed in detail in several recent reviews [14,26,39,66] 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 those incorporating the δ subunit appear to be exclusively extrasynaptic.

NC-IUPHAR [2-3,6,45] class the GABA_A receptors according to their subunit structure, pharmacology and receptor function. Currently, eleven native GABA_A receptors are classed as conclusively identified (i.e., α1β2γ2, α2βγ2, α3βγ2, α4βγ2, α4β2δ, α4β3δ, α5βγ2, α6βγ2, α6β2δ, α6β3δ and ρ) with further receptor isoforms occurring with high probability, or only tentatively [45-46]. It is beyond the scope of this Guide to discuss the pharmacology of individual GABA_A receptor isoforms in detail; such information can be gleaned in the reviews [4-6,20,27,33,36,42,45-46,54,56]. 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 [13,28,43,71].

Several high-resolution cryo-electron microscopy structures have been described in which the full-length human α1β3γ2L GABA_A 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 [40].

The potency and efficacy of many GABA agonists vary between GABA_A receptor isoforms [20,29,36]. For example, gaboxadol is a partial agonist at receptors with the subunit composition α4β3γ2, but elicits currents in excess of those evoked by GABA at the α4β3δ receptor where GABA itself is a low efficacy agonist [9,11]. The antagonists bicuculline and gabazine differ in their ability to suppress spontaneous openings of the GABA_A receptor, the former being more effective [63]. The presence of the γ subunit within the heterotrimeric complex reduces the potency and efficacy of agonists [61]. The GABA_A receptor contains multiple allosteric binding sites. Most drugs modulating GABA_A receptors can bind to several different sites [16]. Distinct allosteric sites bind barbiturates and endogenous (e.g., 5α-pregnan-3α-ol-20-one) and synthetic (e.g., alphaxalone) neuroactive steroids in a diastereo- or enantio-selective manner [8,24-25,65]. Picrotoxinin and TBPS act at an allosteric site within the chloride channel pore to negatively regulate channel activity; negative allosteric regulation by γ-butyrolactone derivatives also involves the picrotoxinin site, whereas positive allosteric regulation by such compounds is proposed to occur at a distinct locus. Many intravenous (e.g., etomidate, propofol) and inhalational (e.g., halothane, isoflurane) anaesthetics and alcohols also exert a regulatory influence upon GABA_A receptor activity [10,44]. Specific amino acid residues within GABA_A receptor α- and β-subunits that influence allosteric regulation by anaesthetic and non-anaesthetic compounds have been identified [23,25]. Photoaffinity labelling of distinct amino acid residues within purified GABA_A receptors by the etomidate derivative, [³H]azietomidate, has also been demonstrated [38], and this binding is subject to positive allosteric regulation by neurosteroids [37]. An array of natural products including flavonoid and terpenoid compounds exert varied actions at GABA_A receptors (reviewed in detail in [27]).

In addition to the agents listed in the table, modulators of GABA_A receptor activity that exhibit subunit dependent activity include: salicylidene salicylhydrazide (negative allosteric modulator selective for β1- versus β2-, or β3-subunit-containing receptors [64]); fragrant dioxane derivatives (positive allosteric modulators selective for β1- versus β2-, or β3-subunit-containing receptors [53]); loreclezole, etomidate, tracazolate, mefenamic acid, etifoxine, stiripentol, valerenic acid amide (positive allosteric modulators with selectivity for β2/β3- over β1-subunit-containing receptors [19,31,33]); tracazolate (intrinsic efficacy, i.e., potentiation, or inhibition, is dependent upon the identity of the γ1-3-, δ-, or ε-subunit co-assembed with α1- and β1-subunits [62]); amiloride (selective blockade of receptors containing an α6-subunit [18]); furosemide (selective blockade of receptors containing an α6-subunit co-assembled with β2/β3-, but not β1-subunit [33]); La³⁺ (potentiates responses mediated by α1β3γ2L receptors, weakly inhibits α6β3γ2L receptors, and strongly blocks α6β3δ and α4β3δ receptors [11,50]); ethanol (selectively potentiates responses mediated by α4β3δ and α6β3δ receptors versus receptors in which β2 replaces β3, or γ replaces δ [68], but see also [32]); DS1 and DS2 (selectively potentiate responses mediated by δ-subunit-containing receptors [67]). It should be noted that the apparent selectivity of some positive allosteric modulators (e.g., neurosteroids such as 5α-pregnan-3α-ol-20-one for δ-subunit-containing receptors (e.g., α1β3δ) may be a consequence of the unusually low efficacy of GABA at this receptor isoform [7,9].

* Key recommended reading is highlighted with an asterisk

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Subcommittee members: Werner Sieghart Center for Brain Research Department of Molecular Neurosciences Medical University Vienna Spitalgasse 4 A-1090 Vienna

Other contributors: Delia Belelli Neurosciences Institute Division of Pathology and Neuroscience University of Dundee Ninewells Hospital and Medical School Dundee DD1 9SY UK Tim G. Hales Center for Neuroscience Division of Medical Sciences Ninewells Hospital and Medical School The University of Dundee Dundee DD1 9SY UK Jeremy J. Lambert Neurosciences Institute Division of Pathology and Neuroscience University of Dundee Ninewells Hospital and Medical School Dundee DD1 9SY UK Bernhard Luscher 301 Life Sciences Building Department of Biology and BMB Pennsylvania State University University Park PA 16802 USA Richard Olsen Department of Molecular & Medical Pharmacology Geffen School of Medicine at UCLA Room CHS 23-120 650 Young Drive South Los Angeles CA 90095 U.S.A John A. Peters Room CB 08 Carnelley Building School of Life Sciences The University of Dundee Dundee DD1 5EH Scotland UK Uwe Rudolph Laboratory of Genetic Neuropharmacology Mclean Hospital and Department of Psychiatry Harvard Medical School 115 Mill Street Belmont MA 02478