ReviewGABAA receptors: Subtypes provide diversity of function and pharmacology
Section snippets
GABAA receptors
Gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the brain, mediates inhibition via GABAA receptors (GABAA-R). These are ligand-gated chloride ion channels that were first identified pharmacologically as being activated by GABA and the selective agonist muscimol, blocked by bicuculline and picrotoxin, and modulated by benzodiazepines, barbiturates, and certain other CNS depressants (Macdonald and Olsen, 1994, Sieghart, 1995). GABAA-R mediate rapid phasic inhibitory
Heterogeneity of GABAA receptors
GABAA receptors are composed of five protein subunits that belong to different subunit classes. There are 19 genes for GABAA-R subunits (Simon et al., 2004). These include 16 subunits (α1–6, β1–3, γ1–3, δ, ɛ, θ, π) combined as GABAA, and 3 rho (ρ) subunits, which contribute to what have sometimes been called GABAC receptors; the latter are considered by the Nomenclature Committee of IUPHAR to be subtypes of GABAA-R containing the ρ subunits, and they recommend against using the term ‘GABAC
Identification of native GABAA receptor subtypes by their regional and cellular distribution
In situ hybridization (Wisden et al., 1992, Persohn et al., 1992) and immunohistochemical studies (Pirker et al., 2000, Fritschy et al., 1992) have indicated that α1, β1, β2, β3, and γ2 subunits are found throughout the brain, although differences in their distribution were observed. Subunits α2, α3, α4, α5, α6, γ1, and δ are more confined to certain brain areas and in some brain regions, a complementary distribution of α2, α4, β3, and δ versus α1, β2, and γ2 subunits was detected (Sieghart and
Identification of native GABAA receptor subtypes by their synaptic and extrasynaptic localizations
Other studies indicated that the individual subunits exhibit a distinct subcellular distribution. For instance, in cerebellar granule cells α1, α6, β2/3 and γ2 subunits have been found by immunogold localizations to be concentrated in GABAergic Golgi synapses and also are present in the extrasynaptic membrane at lower concentration. In contrast, δ subunits could not be detected in synaptic junctions, although they were abundantly present in the extrasynaptic dendritic and somatic membranes (
Identification of native GABAA receptor subtypes by their subunit composition
A variety of GABAA receptor subunit-specific antibodies have been generated and have been used for purifying GABAA receptor subtypes from brain membrane extracts by immunoprecipitation or immunoaffinity chromatography. These studies indicated an extreme promiscuity of the various subunits. Although the antibodies used were highly specific for the respective subunits, most if not all of the other subunits investigated could be co-purified with antibodies directed against an individual α or β
Structural basis of GABAA receptor pharmacology
The GABAA-R are members of the Cys-loop pentameric LGIC superfamily, including nicotinic acetylcholine receptors, inhibitory glycine receptors, and ionotropic 5-HT3 (serotonin) receptors. They differ in structure from two additional LGIC families: the tetrameric glutamate receptors and the trimeric purine receptors (see mini-reviews on these families in this volume). All of the 44 subunit members of the Cys-loop pentameric LGIC superfamily (Collingridge et al., 2009) show sequence homology in
Benzodiazepines
GABAA-R are the site of action of a variety of pharmacologically and clinically important drugs. Their interaction with benzodiazepines has been most thoroughly investigated. The location of the benzodiazepine binding site at the α+/γ− interface indicates that the benzodiazepine pharmacology of receptor subtypes is mainly determined by the α and γ isoforms forming this site. The classical benzodiazepines, such as diazepam or flunitrazepam, predominantly interact with receptors composed of
Which of the many possible GABAA receptor subtypes have been unequivocally identified?
The frequent co-localization of α, β, and γ, or α4/α6, β, and δ subunits in the brain and in synaptic or extrasynaptic sites of specific neurons, respectively, the evidence that these subunits could be co-precipitated from brain membrane extracts, that they form defined recombinant receptors with a specific pharmacology, their identification by receptor binding and electrophysiological studies and the identification of their function using molecular-genetic knock-in or knock-out and
Conclusions
The importance of GABAA-Rs in different brain regions and behaviors has been reinforced in recent years, with recognition that GABAA-Rs come in many different flavors differing in subunit combination, resulting in subtypes that vary in physiology, pharmacology, and most importantly, in location. Both the circuitry and the subcellular location on different postsynaptic and extrasynaptic membranes are important for GABAA-R control of neuronal excitability, and network activity.
As knowledge of
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