GABAA receptors: Introduction

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General

The GABAA receptors are anion channels gated by γ-aminobutyric acid (GABA). Their amino acid sequences lie in the same superfamily as the nicotinic acetylcholine receptors, the glycine receptors, the 5-HT3 receptor, and the anionic glutamate receptors, within the general receptor class of the ligand-gated ion channels (see [2]). Analyses on native brain [34] or recombinant [12,49] GABAA receptors have led to the conclusion that there are five subunits in each receptor molecule. The special problems of the classification of GABAA receptors, based on the subunit structure, assembly and pharmacology, have been discussed by the NC-IUPHAR Subcommittee on GABAA Receptors and in the previous edition of this compendium [3]. Additional data are included here and in a recent review [4].

Subunit types

Cloning from cDNA libraries or genomically has so far generated a total of 19 related GABAA receptor subunits in mammals, which are each encoded by different genes. These fall into eight sequence groups: α1-α6, β1-β3, γ1-γ3, δ, ε, π, θ and ρ1-ρ3 (see refs. [3-4] for their origins and database accession numbers). Mammalian homologues have not yet been investigated for two additional subunits known from the chicken, β4 [29] and γ4 [21], the former illustrating the very strong conservation of the genomic structure of the subunits across the vertebrates. These polypeptides are all approximately 50 000D in size and each carries four putative transmembrane domains (TM).

Subunit heterogeneity is further increased by alternative exon splicing of the pre-mRNA. Two forms of the γ2 subunit [55], which are differently distributed in the mammalian brain [11], are formed from one gene. Two spliced forms are also known for the β2 subunit in the bird [20] and apparently in the mammal [8]. In all of these cases the longer and shorter products are designated 'l' and 's', respectively (e.g. γ2l), and differ by a short peptide sequence in the long intracellular loop between TM3 and TM4, which can alter a regulatory phosphorylation site.

Receptor assembly

The GABAA receptors in the central nervous system are (apart from those containing ρ subunits) formed by drawing upon this repertoire for a total of five subunits per molecule to produce combinations of α and β subunits plus one or more of the γ, δ, θ, π or ε subunit types (or possibly, in certain rare cases, as with some α4 combinations [7], α and β types alone). The majority contain only the αβγ combination. In addition there are three known ρ subunits that occur mainly in the retina and which appear to assemble separately from all others.

Evidence has been presented (reviewed in [3-4]) to suggest that in a minority of the native receptors two different α isoforms can co-occur, or in other cases two β isoforms or two γ isoforms (where only the γ2γ3 pairing is known). Hence the ratio of the subunit types within the pentamers is at present uncertain and might vary depending on the isoforms present.

Modulatory sites

The GABAA receptors contain an exceptional number and variety of modulatory sites where ligands modify the functional response to GABA [30]. The activities of selective ligands at such sites have served as the primary tools for recognising a considerable series of subtypes of this receptor.

Benzodiazepines

A modulatory site that recognises benzodiazepine (BZ) ligands offers by far the richest pharmacology presently known for the definition of subtypes of the GABAA receptors. The majority of GABAA receptors carry some form of this site. Benzodiazepine here means either 1,4-BZ or 1,5-BZ compounds, but not the 2,3-BZ series, which do not act on GABAA receptors. Diazepam is commonly used as representative of a large cohort of 'classical' benzodiazepines (e.g. flunitrazepam, clonazepam, midazolam, etc.) which act similarly, having secondary differences in their activities. BZ ligands have no intrinsic activity on mammalian GABAA receptors, unlike some of the modulators at other sites such as certain anaesthetics. Benzodiazepines generally act to enhance the action of GABA, but some drugs can act in the opposite direction at this site, i.e. they are inverse agonists, having negative modulatory efficacy.

Drugs with functional similarities to benzodiazepines

Benzodiazepines themselves are usually rather poor tools with which to make the subtype distinctions and a range of non-benzodiazepine compounds of very varied structures, but with modulatory activities at the BZ site, are more effective and are now more widely used. These include triazolopyridazines, pyrazoloquinolines, imidazopyridines, imidazopyrimidines, cyclopyrrolones, β-carbolines, etc. (a list of 18 heterocyclic classes containing members with such activities, and the names and structures of all of the commonly used 'BZ-like' drugs, are presented in [3]). A variety of pharmacologies can be distinguished using these modulators as probes, acting as either positive or inverse agonists [3]. Certain compounds, exemplified by flumazenil, Ro154513, CGS8216 or RP60503, can act at many of the subtypes as antagonists or near-antagonists at this site (the first two can be used in radioligand binding studies to identify the BZ-sensitive GABAA receptors).

From a wide range of studies of recombinant αβγ receptors, expressed either in Xenopus oocytes or in transfected mammalian cells, it has been found that a γ subunit is required for the sensitivity to BZ-like drugs [40,42], while the α subunit isoform present exerts a major effect on the affinity and efficacy of such ligands [39,42,47,50,52-53]. Thus the presence of α1 or α2 or α3 or α5 subunits gives rise to a range of quantitative differences in the responses to BZ--like positive agonists (see [3]). As one example, the imidazopyridine zolpidem displays GABA-modulatory affinity and efficacy which are high on α1βγ2 receptors but very low on α5βγ2 receptors [16]. If the α4 or α6 isoforms are used in αβγ combinations, a different type of activity is produced [3,23,27,45,47,52]. The effect varies considerably with the modulator, but classical benzodiazepine agonists exhibit greatly reduced or negligible affinities and potentiations. However, some of the partial agonists (such as bretazenil) on the former combinations become fuller agonists on the α4βγ2 or α6βγ2 receptors. BZ-like ligands, which act on the former types as inverse agonists, can become partial positive agonists on the two latter types of subunit combinations (as with Ro154513), or they may become antagonists, as with DMCM at the α6βγ2 combinations. Flumazenil, otherwise an antagonist, becomes a weak partial agonist on both the α4 and α6 types.

The isoform of the γ subunit that is present can modify the effect of the α isoform. The γ2 subunit mRNA is much more abundant in the brain than that for γ3 or γ1, and the predominance of the γ2 subunit is confirmed by the results seen with transgenic mice in which the γ2 subunit is deleted, leading to an almost total extinction of the BZ-binding sites and of the benzodiazepine-sensitivity of the brain GABAA receptors [18]. There is reduced positive modulation by most BZ-like agonists when γ2 is replaced by γ1, while inverse agonists (e.g. some β-carbolines) then become agonists [42,53]. Flumazenil and Ro154513 are bound much more weakly when γ1 is present and change from very strong antagonists to agonists of low or negligible potency at the BZ site [42,53]. Hence for each candidate receptor in the α series the γ1 subunit-containing receptors are classified separately from those with γ2. A similar but lesser weakening with several BZ-like agonists is known for the replacement of γ2 by γ3, in the α1- and α5 subunit-containing receptors, while with α1βγ3 zolpidem becomes almost inactive [19,47].

Benzodiazepine insensitivity

A considerable minority of GABAA receptors detected in the nervous system are not modulated at all at the BZ site. These must be distinguished from the 'diazepam-insensitive' type, which are not modulated by, and do not bind, the classical BZ positive modulators (e.g. the α4βγ and α6βγ series, where some form of the BZ site is still present). The classification, therefore, includes an 'A0' class for receptors completely insensitive to BZ-like drugs. This can arise by different molecular mechanisms, giving subtypes GABAA01, GABAA02, etc. One form of insensitivity at this site would arise from the absence of any γ subunit , as found in some of the native α4-containing receptors [7], although the resultant composition is as yet uncertain. More common cases would be the ρ-containing receptors, or the presence of a δ or ε or ρ subunit along with α and β subunits but no γ subunit. The latter three groups of receptors retain the classical antagonism by bicuculline, whereas the ρ-containing receptors are distinguished by its absence.

The δ and ε subunits appear to replace a γ subunit in some receptors. The δ subunit protein in the rat brain is prominent only in the cerebellar granule cells and in the thalamus and olfactory bulb [17,48]. In the cerebellum δ has been localised by high-resolution antibody methods in extra-synaptic α6βδ or α6α1βδ combinations only [37]. Immunopurification analyses have likewise shown that these two, present in about equal amounts, account for all of the cerebellar δ subunits [24], both being BZ-insensitive. In the thalamus (or elsewhere) such analyses show that δ is in a BZ-insensitive α4βδ combination only [7,48]. Recombinant αβδ combinations can, indeed, form GABA-gated channels, which are insensitive to diazepam and DMCM [44].

Likewise, heterologous expression studies with the ε subunit [13,35,56] have shown that (at least) α2β1ε or α1β3ε or α1β1ε combinations, activated by GABA, can be formed. These are not modulated by diazepam and desensitize much more rapidly than α1β1 or α1β1γ2 receptors.

The π (for 'peripheral') subunit has been found present in several human peripheral organs, principally the uterus, and in very low levels in hippocampus and cortex [22,36]. In heterologous co-expressions evidence for the formation of BZ-insensitive α1β1γ2π, α5β3π and α5β3γ3π receptors was obtained. The ability of π to inactivate the BZ site in the presence of γ2 is exceptional. The function of π in vivo is still uncertain.

The θ subunit [10] is prominent in certain regions of primate brain, particularly in the substantia nigra and the striatum, and absent in most others. It is associated with dopaminergic or noradrenergic neurones. Exceptionally, θ assembles (so far as was detectable from co-immunoprecipitation of rat striatal extracts) with one α isoform only, α2, and with γ1 and not with γ2, γ3, δ nor ε. It was concluded [10] that the preferred θ combination in the striatum is α2β1γ1θ. Functional heterologous expression of θ required a quaternary set, αβγδ; however, α2 or α1, and γ1 or γ2 were also active. Modulation by BZ-like agonists or inverse agonists, or by pentobarbital or pregnanolone, were all unchanged by θ incorporation.

The ρ-containing receptors

These receptors are formed from the ρ1, ρ2 and ρ3 subunits. ρ1 and ρ2 are expressed predominantly in the retina [14-15,54] and appear to be post-synaptic [14]. All occur also in several brain regions, while rat ρ3 mRNA is expressed more in the hippocampus than in the retina [38,54]. The receptors containing ρ subunits form another class insensitive to all BZ-like drugs, but these are distinguished also by their insensitivity to bicuculline as well as to the GABAA receptor agonist isoguvacine and by their activation by cis-4-aminocrotonic acid [25]. These have previously been referred to as 'GABAC receptors', but since the ρ subunits are 30-40% identical in sequence to the other GABAA receptor subunits, within the range found for other subunit family comparisons, they are now designated by NC-IUPHAR as a subclass of the GABAA receptors, of the 'A0' type, i.e. A0r (where r denotes the ρ subunit, for database use). This also removes the anomaly of separating these two branches of the ionotropic GABA receptor family as GABAA and GABAC receptors, with a metabotropic family, GABAB, lying between them. In co-expressions so far as has been investigated, the ρ subunits cannot participate in combinations with the α, β or γ types. Instead, the heterologous expression of each of ρ1, ρ2 and ρ3 alone can give strong functional expression, such that native ρ homo-oligomers have been assumed. However, this must now be reconsidered, since in recombinant co-expressions rat [58] and human [15] ρ1ρ2 and also ρ2ρ3 [38] heteromeric receptors form, functionally distinct from any of the homo-oligomers, and ρ1ρ2 can mimic better than the latter the retinal A0r receptors [58]. The range of ρ-containing compositions at all their sites in vivo cannot yet be specified.

Other modulatory sites

For some of the numerous other, distinct modulatory sites detected on GABAA receptors [3,30,47], ligands have been discovered that can show a preference for particular subunit isoforms and even select one or a few of the possible receptor subunit combinations. Thus, the anti-convulsant drug loreclezole is a GABA-potentiating ligand that does not act at the benzodiazepine site but which is able to recognise the presence of β2 or β3 but not β1 subunits [51]. It acts in all of the αβ2/3γ combinations tested (although, exceptionally, on α5β3γ3 only at very low GABA concentrations [36]), and even when the π subunit is also incorporated [36] or when a γ subunit is replaced by ε [35]).

A number of anaesthetics (both volatile and intravenous) and neuroactive steroids (endogenous, such as 5α-pregnan-3α-ol-20-one, or synthetic, e.g. alphaxolone) are also modulators of GABAA receptors [30,47]. While nearly all are positive modulatory agonists, inverse agonist effects are also known in these series [6,31,57] and in some cases direct activation also occurs at higher drug concentrations. High selectivity is commonly not found: both α and β subunits carry such modulatory sites [9,32,43], albeit with quantitative differences between their isoforms which vary with the drug [26,33,41,43,46,57], while the γ subunit is not required for the modulatory action of any of the anaesthetics or neurosteroids [9,26,32,43,46,56-57]. When ε or π subunits replace γ, or when θ is present with γ, the receptors still maintain these modulations [10,35-36,56]. However, some specificities are known. Thus, addition of the δ subunit removes the neurosteroid sensitivity of α4β or α6β pairs [59]. For sensitivity to the anaesthetic etomidate there is a strong preference for a β2 or β3 over a β1 subunit [5,33,43], which mutation of a residue in the β subunit TM2 affects [5,33]. The same position in TM2 is critical in β1, α1 or α2 for modulation by volatile anaesthetic drugs but not by several intravenous types (propofol, methohexital, alphaxolone) [28,32] and in ρ1 it can govern insensitivity to pentobarbitone but not to propofol or neurosteroids [6]. Mutations in the same subunits at certain other positions can also show some of these effects [1,9,28,32] so the relationship of this position to an anaesthetic binding site may not be direct. The ρ subunits are totally insensitive to all of the drugs considered here, but a point mutant [6] and chimeras of ρ and a non-ρ subunit [32] suggest that these differences may arise from very few sequence changes and emphasise that the ρ-containing receptors are not fundamentally different to the rest of the GABAA receptors.

Concluding remarks

In assessing possible combinations of subunit types to form a mammalian GABAA receptor, it is clearly important to consider all the subunit isoforms, including their spliced variants where they are known. Although the possible combinations of subunits to form a functional receptor molecule are limited in the ways described, and locally restricted co-expressions of subunit types in situ must generally occur, a widevariety of GABAA receptors could exist in vivo. The total number is unknown but potentially still considerably higher than for any other presently known receptor type, with the possible exception of the special case of the olfactory receptors.

Unlike most, perhaps all, other receptor types, it is possible to create in vitro many more forms of the GABAA receptor than are likely to exist in the native state. Each should be accepted, even provisionally, as a receptor type only where there is evidence for its in situ occurrence. An initial list of 18 combinations, which can be recognised on this basis as distinct types (including only ρ1ρ2 from the ρ set), has been published by the subcommittee [3]. This is still a provisional list because, apart from all other considerations, the internal stoichiometry cannot be stated for a single native receptor.

References

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To cite this family introduction, please use the following:

Richard Olsen, John A. Peters, Tim G. Hales, Werner Sieghart, Uwe Rudolph, Jeremy J. Lambert, Delia Belelli, Bernhard Luscher.
GABAA receptors, introduction. Last modified on 06/03/2014. Accessed on 17/01/2019. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/FamilyIntroductionForward?familyId=72.