GABAA Receptors

Abstract

GABAA receptors are fast‐acting, ligand‐gated anion channels that are the major mediators of inhibitory neurotransmission in the mammalian central nervous system. GABAA receptor activity is regulated by phosphorylation as well as being modulated allosterically by a variety of drugs including the anxiolytic benzodiazepines and barbiturates.

Keywords: GABAA receptors; ligand‐gated ion channel superfamily; benzodiazepines; neurotransmitter receptor; barbiturates

Figure 1.

A summary of the pertinent features of GABAA receptors. (a) The known GABAA receptor genes. (b) The transmembrane topology of GABAA receptor polypeptides. ↓, sites for N‐glycosylation; C‐C, the cys–cys loop, the conserved extracellular motif characteristic of members of the ligand‐gated ion channel superfamily; TM1–TM4, transmembrane‐spanning regions; P, sites for phosphorylation. (c) Schematic view of the GABAA receptor as viewed perpendicular to the plane of the membrane. Each of the five subunits of the receptor is represented as a segment within the annular structure; the hole in the centre represents the chloride ion channel. The four TM regions within each polypeptide are shown as filled circles, with the predicted α helix of TM2 lining the wall of the channel.

Figure 2.

Simplified schematic model of the major type of GABAA receptor expressed in adult mammalian brain highlighting amino acids implicated in ligand binding. The subunit stoichiometry most consistent with all published experimental results is (α1)2(β2/3)2(γ2)1. The figure shows an α1 (green), β3 (blue) and γ2L (yellow) subunit with the binding pocket for GABA at the interface of the α and β subunit and residues important for benzodiazepine subpharmacology at the interface between the α and γ subunit. Note that in accord with the studies of the Unwin group (Miyazawa et al., ) on the peripheral nicotinic acetylcholine receptor, the GABA‐binding site is depicted as approximately half way down the extracellular region. It is unclear whether GABA binds on the outer surface of the protein or from within the channel. The leucine residues (L) in the transmembrane region, TM2, are those conserved with the nicotinic receptor which for that protein have been identified as the gate within the channel lumen. This GABAA receptor will have type‐I benzodiazepine pharmacology and, additionally, it is loreclezole‐sensitive. Amino acids identified as targets for protein kinase A phosphorylation are depicted as S; protein kinase C phosphorylation in γ2L as circled S; and tyrosine kinase, Y. 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. Reproduced with permission from Stephenson, FA (1995) Biochemical Journal310: 1–9. Copyright, Biochemical Society.

Figure 3.

The predicted secondary structure of the extracellular region of an α2β2γ1 GABAA receptor together with the localization of the GABA and benzodiazepine ligand‐binding pockets. α subunits are green, β subunits blue, the γ subunit, yellow; the secondary structure shows both α helical and β sheet regions. (a) is the view from the top of the protein looking down into the ion channel pore. Two molecules of GABA are shown at the α/β subunit interfaces. They have been fitted into the site on the basis of known, published interactions. Residues that have been implicated experimentally in the GABA binding site from the β subunit and the α subunit and the benzodiazepine site from the α and γ subunits are shown as sticks. (b) is a view of the same structure rotated through 90° so that the membrane is now at the bottom of the image. The α and β subunits and the GABA molecule at the rear of the pentamer are coloured grey. Residues that are implicated in one of the putative binding sites and in the benzodiazepine site are indicated as in (a). (c) is GABA; (d) the benzodiazepine, flunitrazepam; and (e) muscimol, the potent GABAA receptor agonist. Loop 7, the cys–cys loop, implicated in the chloride channel gating mechanism is adjacent to membrane and indicated by the arrow in (b). Reproduced with permission from Cromer et al..

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References

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Further Reading

Barnard EA, Skolnick P, Olsen RW et al. (1998) International Union of Pharmacology. XV. Subtypes of γ‐aminobutyric acidA receptors: classification on the basis of subunit structure and receptor function. Pharmacological Reviews 50: 291–314.

Betz H (1998) Gephyrin, a major player in GABAergic postsynaptic membrane assembly. Nature Neuroscience 1: 541–543.

Sieghart W (1995) Structure and pharmacology of γ‐aminobutyric acidA receptor subtypes. Pharmacological Reviews 47: 181–234.

Sigel E and Baur A (1997) The benzodiazepine binding site of GABAA receptors. Trends in Pharmacological Sciences 18: 425–429.

Smith GB and Olsen RW (1995) Functional domains of GABAA receptors. Trends in Pharmacological Reviews 16: 162–168.

Stephenson, FA and Turner, AJ (eds) (1998) Amino Acid Neurotransmission. London: Portland Press.

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Stephenson, F Anne(Jan 2006) GABAA Receptors. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1038/npg.els.0004058]