Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

GABAA Receptor

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_430


Historical Background

γ-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the mammalian brain, where it was first discovered in 1950. It is a small zwitterionic γ-amino acid with molecular weight of 103 g/mol (Fig. 1). Such a hydrophilic molecule cannot cross the blood brain barrier. It is produced in the brain by decarboxylation of L-glutamate by the enzyme glutamic acid decarboxylase (GAD). GABA was recognized as an inhibitory transmitter in 1967. It interacts with two types of receptors: ionotropic GABA A receptors (GABA ARs) that are fast-acting ligand-gated chloride channels, and metabotropic GABAB receptors that are coupled indirectly via G Proteins to either Ca2+ or K+ channels to produce slow and prolonged inhibitory responses. The first GABAAR subunits were cloned in 1987. Since then, molecular biological, electrophysiological, and pharmacological studies have revealed the highly heterogeneous nature of GABAARs (Olsen and Sieghart 2008; Froestl 2011).
GABAA Receptor, Fig. 1

γ-Aminobutyric acid (GABA) is the principal inhibitory neurotransmitter in the mammalian brain

Structure of GABAA Receptors

GABAARs belong to Cys-loop superfamily of ligand-gated ion channels. In addition, the Cys-loop receptor superfamily comprises the nicotinic acetylcholine receptors, the glycine receptors, the 5-hydroxytryptamine3 receptor, and zinc-activated cation channel. The subunits of Cys-loop receptors share a common primary structure consisting of large extracellular domain with a “signature” disulfide, four transmembrane segments (TM), and a large variable cytoplasmic domain (cytoplasmic loop) between TM3 and TM4 (Fig. 2). The secondary and three-dimensional structures of the subunits and the quaternary pentameric assembly of the subunits are also well conserved within the superfamily.
GABAA Receptor, Fig. 2

Secondary structure of a GABAA receptor subunit. The subunit consists of a large extracellular domain containing the signature disulfide loop, four transmembrane domains, and a large intracellular domain between TM3 and TM4

Mammalian GABAARs are assembled from 19 subunits that belong in 8 subunit classes according to sequence similarity: α1–α6, β1–β3, γ1–γ3, δ, ε, π, θ, and ρ1–ρ3 (Olsen and Sieghart 2008). Each subunit is encoded by a homologous but separate gene. The subunits produce heteropentameric receptor complexes (Fig. 3). Most GABAARs consist of α, β, and γ subunits with a subunit stoichiometry of 2α:2β:1γ (Olsen and Sieghart 2008). The γ2 subunit is the γ isoform present in more than 90% of receptors. Thus, 75–80% of GABAARs contain γ2 (Whiting 2003). γ2 Subunit in the receptor complex confers sensitivity to benzodiazepines. The αβγ receptor subtypes clearly identified in the brain thus far consist of each α subunit isoform in combination with β and γ2 subunits (Fig. 3). The α1 is the most abundant α subunit; it is present in most brain regions and its expression colocalizes with those of β2 and γ2. Thus, the α1β2γ2 receptor subtype comprises 40–50% of brain GABAARs (Olsen and Sieghart 2008). Subunits α4 and α6 combine with β and δ subunits to form α4βδ and α6β2δ receptor subtypes that are localized extrasynaptically (Fig. 4). Receptor subtypes existing with high probability include αβγ receptors containing either the γ1 or γ3 subunit; receptors containing only α and β subunits (αβ); and αβγ or αβδ receptors containing two different α or β variants (Olsen and Sieghart 2008). Rho subunits form homomeric and heteromeric ρ pentamers. Epsilon and θ are believed to combine with other classes of GABAAR subunits to form receptors, but the native receptor combinations are currently not known. The π subunit is expressed outside CNS and forms homo-oligomeric complexes (Fig. 3) (Olsen and Sieghart 2008; Uusi-Oukari and Korpi 2010).
GABAA Receptor, Fig. 3

GABAA receptor subunits combine to form various GABAA receptor subtypes. A part of the combinations has been shown to exist in native brain, while the presence of other combinations have been deduced from similarities between the subunits in mRNA expression patterns and in immunochemical experiments showing similar localization of the subunits

GABAA Receptor, Fig. 4

Synaptic GABAA receptors form synaptic clusters in the postsynaptic membrane. Extrasynaptic receptors are localized in extrasynaptic parts of the cell membrane. Synaptic receptors are activated by high concentration of presynaptically released GABA, while extrasynaptic receptors are activated by ambient GABA present in the interstitial space

Regulation of GABAA Receptor Expression

The large number of GABAAR genes and the various types of neurons and glial cells in the brain with different patterns of subunit expression suggest a complex system regulating their transcription (Laurie et al. 1992a; Wisden et al. 1992; Olsen and Sieghart 2008). Major changes occur during development in the subunit expression patterns (Laurie et al. 1992b). Changes in receptor subunit expression also take place in adult brain. The changes are often suggested to reflect changes in neuronal activity. Activity-dependent signaling pathways modulate the function of both transcriptional activators and repressors, but the transcription factors responsible for the developmental and brain region/cell-specific expression of GABAAR subunits are presently unknown. Calcium is a crucial second messenger in the transduction of synaptic activity into gene expression, and it is involved in the mechanisms of GABAAR up- and downregulation (Gault and Siegel 1998; Lyons et al. 2001). Some mechanisms regulating α1 mRNA transcription have been revealed recently. The transcription factor cAMP Response Element Binding Protein (CREB) is induced in response to stimulation with neurotransmitters, neuromodulators, and neurotrophic factors. Activation of Protein Kinase C (PKC) in primary rat neocortical cultures increases transcription of α1 mRNA via phosphorylation of CREB that is bound to the GABRA1 promoter (Hu et al. 2008). In contrast, activation of Protein Kinase A (PKA) represses α1 mRNA transcription via Inducible cAMP Early Repressor (ICER) that forms inactive heterodimers with CREB (Hu et al. 2008). Brain-Derived Neurotrophic Factor (BDNF) decreases α1 transcription via activation of the Janus Kinase/ Signal Transducer and Activator of Transcription (STAT) pathway (Lund et al. 2008). BDNF-dependent phosphorylation of STAT3 induces the synthesis of ICER that binds with phosphorylated CREB at the GABRA1 promoter CRE site, thereby repressing transcription (Lund et al. 2008). BDNF has been shown to regulate transcription and cell surface expression of many GABAAR subunits, the effects being brain region- and subunit-specific (Uusi-Oukari and Korpi 2010).

Cell surface expression of GABAARs includes various interacting proteins affecting receptor cell surface expression and postsynaptic accumulation. Heterodimers of α and β subunits are initially formed in a process involving interaction with endoplasmic reticulum (ER) – associated chaperones calnexin and binding immunoglobulin protein (BiP). Heteropentameric GABAARs assembled in the ER are stabilized with ubiquitin-like protein Plic-1 that interacts with α and β subunits and facilitates the exit of assembled receptors from ER to the Golgi. GABAAR Eγ2 subunit is palmitoylated at cytoplasmic cysteine residues by the Golgi resident palmitoyltransferase GODZ, thus promoting translocation of receptors through the Golgi apparatus to the plasma membranes and to synapses. BIG2, a GTP exchange factor (GEF), is implicated in facilitating exit of GABAARs by interacting with β subunits. Translocation of GABAARs to the cell surface is further facilitated by several proteins including GABARAP (interacts with GABAAR γ subunits), N-ethylmaleimide-sensitive factor (NSF), and glutamate receptor interacting protein (GRIP). Postsynaptic clustering of GABAAR subtypes α1βγ2, α2βγ2, and α3βγ2 is facilitated by interaction of α1-α3 subunits with gephyrin, a multifunctional protein that serves as a subsynaptic scaffold organizing the spatial distribution of receptors and other proteins in inhibitory postsynaptic membranes. In addition, gephyrin-binding motifs have been identified in large cytoplasmic loops of β2 and β3. The interaction of α1-3βγ2 GABAARs with the postsynaptic cytoskeleton is regulated by the activity-dependent and calcineurin-regulated phosphorylation state of γ2 subunit. Transmembrane domain 4 and intracellular domain of the γ2 subunit have been shown to be necessary for recruiting gephyrin to the synapse. The role of gephyrin is to stabilize clustered GABAARs at the cell surface (Luscher et al. 2011; Vithlani et al. 2011; Mele et al. 2016).

GABAAergic Signaling Is Developmentally Shifted from Depolarizing (Excitatory) to Hyperpolarizing (Inhibitory)

In prenatal and early postnatal stage of the development, the intracellular Cl concentration ([Cl]i) of immature neurons is higher than that of the extracellular space. This is due to high expression of the cation-chloride cotransporter NKCC1 that accumulates Cl inside the cells by an energy-dependent transport process (Fig. 5). Thus, GABAAR activation at an early stage of development results in Cl efflux via the receptor-associated anion channel and in subsequent depolarization of the cell membrane. Excitatory GABAAR activity regulates neuronal proliferation, migration, differentiation, and neuronal network formation and remodeling. The depolarizing activity of GABA activates voltage-dependent Ca2+ channels, relieves Mg2+ blockade of N-Methyl-d-Aspartate Receptors (NMDAR), and can lead to generation of action potentials (Ben-Ari et al. 2007).
GABAA Receptor, Fig. 5

In immature neurons the [Cl]i is higher than that in extracellular space. The chloride efflux via GABAA receptors along chloride concentration gradient results in depolarization of the cell membrane. In mature neurons the [Cl]i is lower than [Cl] in extracellular space. Thus, chloride influx via GABAA receptors along chloride concentration gradient results in hyperpolarization of the cell membrane. High intracellular [Cl]i in immature neurons is due to high and low expression levels of NKCC1 and KCC2 transporters, respectively. In mature neurons, the expression levels of NKCC1 and KCC2 are opposite to that in immature cells resulting in low [Cl]i

During brain development, GABA signaling is established before glutamatergic transmission, suggesting that GABA is the principal excitatory transmitter during early development. GABAARs are expressed well before synapses are formed. GABA is released at an early developmental stage and acts as a trophic factor to modulate several essential developmental processes including neuronal proliferation, migration, differentiation, synapse formation, neuronal growth, and network construction. This early intercellular communication is based on diffusion and distal paracrinic actions that contrasts with the local fast communication provided by synaptic currents. GABA tonically reduces the speed of cell migration via GABAAR activation. Astrocytes may generate a microenvironment that controls the degree of GABAAR activation and the migration of neuronal precursors (Ben-Ari et al. 2007; Oh et al. 2016).

Proliferation of neocortical progenitors in ventricular and subventricular zones of the developing cortex is downregulated by GABAAR activation that leads to depolarization of plasma membrane and increase in intracellular Ca2+. The interneuronal precursors synthesize and release GABA, and express GABAARs to respond to the secreted GABA. Cortical entry of tangentially migrating interneuronal precursors arriving from the medial ganglionic eminence is enhanced by GABA and GABAARs. This enhanced motility of interneurons is dependent on GABAAR-mediated depolarization and downstream activation of L-type calcium channels. However, soon after interneurons enter the cortex, their spontaneous calcium oscillations and their migration terminate. This is due to an increase in the expression of KCC2 transporter which reduces the [Cl]i and terminates depolarizing activity of GABAARs (Jovanovic and Thomson 2011).

Developmental changes in GABA signaling are determined by the progressive negative shift in EGABA that in turn reflects the developmental reduction of intracellular [Cl]i. KCC2 is the principal transporter for Cl extrusion from neurons. KCC2 extrudes K+ and Cl using the electrochemical gradient for K+. Cl extrusion is weak in immature neurons and increases with neuronal maturation. The KCC2 is strongly expressed in mature neurons (while the expression of NKCC1 is strongly downregulated), thus underlying the developmental changes in Cl extrusion. K+-Cl cotransport also contributes to the low [Cl]i in mature neurons. Developmental expression of KCC2 is pivotal for development of hyperpolarizing GABAAR-mediated inhibition (Ben-Ari et al. 2007).

Synaptic (Phasic) and Extrasynaptic (Tonic) GABAA Receptor-Mediated Inhibition

The receptor subtypes α1-3βγ2 form clusters in synapses. They are activated with a very high local concentration of presynaptically released GABA. A large number of clustered synaptic receptors are activated very quickly and their desensitization is also fast. In contrast to α1-3βγ2 combinations that are clustered in synapses, α5βγ2 receptor subtype is predominantly clustered extrasynaptically by interaction with phospho-activated radixin, which links these receptors to submembrane microfilaments (Luscher et al. 2011). Part of αβγ2 receptors are freely moving in extrasynaptic portion of plasma membrane. In addition to α4βδ and α6βδ receptors that are localized exclusively extrasynaptically, part of each αβγ2 receptor subtypes contribute, in addition to αβδ receptors, to the production of the continuous tonic inhibition (Fig. 4). α4/6βδ receptors are particularly suited for tonic activity, because they possess high affinity for GABA and are thus activated by the ambient GABA leaking out from synapses or released extrasynaptically. In addition, α4/6βδ receptors desensitize very slowly, therefore being tonically active (Luscher et al. 2011; Belelli et al. 2009).


In addition to production of receptor subtype-selective drugs with minimal adverse effects, one of the major challenges in GABAAR research is to resolve the signaling molecules and pathways responsible for developmental and brain region/cell-specific regulation of GABAAR subunit and receptor subtype expression. The work is already in progress and new challenges are arising from the progression.


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© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Department of Pharmacology, Drug Development and Therapeutics, Institute of BiomedicineUniversity of TurkuTurkuFinland