GABAA Receptors


GABAA (gamma‐aminobutyric acid) receptors are fast‐acting, ligand‐gated anion channels that are the major mediators of inhibitory neurotransmission in the mammalian central nervous system as well as essential elements in many nonneuronal cells. A large number of receptor subtypes arise from many subunit classes and isoforms and their respective splice variants. They share many structural and functional attributes with the other members of the pentameric ligand‐gated ion channel superfamily. At this time, the precise number and structures of native receptor subtypes are still not known. GABAA receptor subtype activity is additionally regulated by phosphorylation as well as being modulated allosterically by a variety of small molecules including benzodiazepines, chemically very diverse plant compounds, endogenous and synthetic neuroactive steroids and many more. Genetic or adaptive alterations in subunit primary structures, expression or receptor function have been implicated in many phenotypes.

Key Concepts

  • Nineteen mammalian GABR genes and their splice isoforms encode GABAA receptor subunits that are assembled into glycosylated homo or heteropentameric GABA‐gated anion channels, constituting the largest family of mammalian ligand‐gated ion channels.
  • Expression of GABR genes is tightly regulated during development, uniquely different for individual cell types and modulated by internal and environmental stimuli ranging from hormonal status to factors such as temperature, stress or many medications.
  • Genetic findings imply altered GABAA receptor signalling to be a contributing factor to many different phenotypes including diverse epilepsies, addiction risks and many more.
  • GABAA receptor subunits share a common domain organisation with all other members of the pentameric ligand‐gated ion channel superfamily comprising a large extracellular domain, a transmembrane domain of four transmembrane helices (M1–M4) and an intracellular domain that is highly variable and contains a multitude of regulatory and protein–protein interaction sites.
  • On each pentamer, depending on its subunit composition, one to five agonist binding sites and many allosteric binding sites exist that impart on each GABAA receptor subtype a uniquely distinct pharmacological profile.
  • The transient kinetic properties of GABAA receptors depend on the subunit composition, absence or presence of allosteric modulators such as neuroactive steroids and the phosphorylation state of the individual subunits.
  • Synaptic GABAA receptors are clustered at the postsynaptic membrane and mediate phasic inhibition, namely a fast response to presynaptic GABA release.
  • Extrasynaptic GABAA receptors that are located away from synapses mediate tonic inhibition and are continuously activated by varying low concentrations of GABA, and thus regulating neuronal excitability.

Keywords: GABAA receptors; pentameric ligand‐gated ion channel superfamily; cys‐loop receptors; allosteric modulation; benzodiazepines

Figure 1. The human GABAA receptor subunit genes and their relationship and pentameric assembly into known and putative receptors. The phylogenetic tree in the centre depicts the degree of similarity (based on % sequence identity of the primary structures) of the 19 GABR genes. In humans, Chromosome 5 harbours a gene cluster with GABRa1, GABRa6, GABRb2, GABRg2 and GABRp; Chromosome 4 harbours a homologous cluster with GABRa2, GABRa4, GABRb1 and GABRg1; on Chromosome 15, we find GABRa5, GABRb3 and GABRg3, the X‐Chromosome contains GABRa3, GABRq and GABRe; Chromosome 6 contains GABRr1 and GABRr2 and GABRd is on Chromosome 1 and GABRr3 on Chromosome 3. A total of 28 possible pentamer arrangements is depicted to provide a qualitative impression of the vast possibilities. The arrangements are numbered and their identifier is in the centre of each pentamer, starting at the left upper corner. The colour of each number indicates a relative degree of probability for existence in vivo (blue for ‘proposed to exist’, red for ‘exist with high probability’ and green for ‘putative’). Pentamers 1–3 depict homopentameric examples, different items of evidence support their physiological existence. Examples of ‘binary’ receptors assembled from subunits of two different classes (such as αxβy) or two members of a class (ρ1ρ2) are shown in assemblies 4–8. The major group of CNS (central nervous system) receptors, ‘ternary’ αxβyγz receptors are depicted in assemblies 9–14, whereby the standard pentamer stoichiometry and arrangement are depicted in 9–13, while 14 shows an alternative stoichiometry which has also been discussed by some investigators. Pentamers 15–21 depict diverse δ‐containing arrangements that have been investigated, whereby 15 and 16 display two of the arrangements that have been proposed for the ‘same’ receptor entity that is thought to consist of two α4, two β3 and one δ subunit. It is at this time unclear if different techniques produce different pentameric assemblies, or if physiological assemblies containing δ subunits also feature very diverse stoichiometries and arrangements. Putative pentamers incorporating θ and ϵ subunits are depicted in 22 and 23, ρ‐ and ργ‐containing arrangements in 24–26 and π‐containing assemblies in 27 and 28. Subunits without identity are displayed as a reminder that very little is known about the assembly partners of the less studied receptor subunits. Often cited ‘rules’ such as β subunits being replaced by θ, and γ subunits being substituted by ϵ, as depicted in arrangements 22 and 23, have so far not been verified in receptors derived from a natural source.
Figure 2. The structure (a) and topology (b) of the typical GABAA receptor subunit polypeptides, based on the 4COF and 4PIR crystal structures. Both experimental structures are incomplete, 4COF lacking the entire ICD (intracellular domain) and 4PIR lacking part of it. This image is based on the assumptions that HX may also be present in some GABAA receptor subunits, and HA is likely to be conserved. The dashed lines indicate that the missing ICD fragment is highly variable in primary structure sequence and length, and thus, subunits will have uniquely different ICD domains. Pertinent features are labelled and/or colour coded: The cys‐loop is shown in yellow in the otherwise lilac ECD (extracellular domain), ECD interface binding site‐forming segments A–G are indicated in the topology diagram with green capital letters. The junction zone loops and the C‐terminus are coloured in grey, the four TMD (transmembrane domain) helices and the HX helix, which in the homologous cation channels is located in the TMD as well, are coloured in red, while the structural parts that are localised intracellularly are coloured green. The HX and HA regions contain (irrespective of their true structure) several interaction sites for trafficking proteins (Luscher et al., ), and the entire ICDs can harbour phosphorylation sites and interaction sites with clustering proteins (Luscher et al., ), all of which are highly specific for individual subunits. For example, GABARAP, gephyrin and GRIF‐1 are GABAA receptor‐associated proteins thought to be involved in the trafficking (GABARAP and GRIF‐1) and clustering (gephyrin) at inhibitory synapses.
Figure 3. Simplified schematic model of a prototypical GABAA receptor pentamer with known and putative small molecule binding sites. The figure shows at the interface between a principal (P) and a complementary (C) subunit those small molecule binding sites for which structural evidence in different cys‐loop receptors has been presented, (see also Table and Puthenkalam et al., ). If P is a β subunit and C is an α subunit, site a would be the GABA site. Correspondingly, if P is an α1 subunit and C a γ2 subunit, sites a and b together form the binding pocket of benzodiazepine‐site ligands such as diazepam or zolpidem at the interface between the α and γ subunits. Table provides a list of ligands and ligand candidates for all depicted sites.


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Further Reading

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Ernst, Margot, Steudle, Friederike, and Bampali, Konstantina(Jan 2018) GABAA Receptors. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0000233.pub3]