F
IPR006028

Gamma-aminobutyric acid A receptor/Glycine receptor alpha

InterPro entry
Short nameGABAA/Glycine_rcpt
Overlapping
homologous
superfamilies
 
family relationships

Description

Gamma-aminobutyric acid type A (GABAA) receptors are members of the neurotransmitter ligand-gated ion channels: they mediate neuronal inhibition on binding GABA. The effects of GABA on GABAA receptors are modulated by a range of therapeutically important drugs, including barbiturates, anaesthetics and benzodiazepines (BZs)
[4]
. The BZs are a diverse range of compounds, including widely prescribed drugs, such as librium and valium, and their interaction with GABAA receptors provides the most potent pharmacological means of distinguishing different GABAA receptor subtypes.

GABAA receptors are pentameric membrane proteins that operate GABA-gated chloride channels
[7]
. Eight types of receptor subunit have been cloned, with multiple subtypes within some classes: alpha 1-6, beta 1-4, gamma 1-4, delta, epsilon, pi, rho 1-3 and theta
[3, 5]
. Subunits are typically 50-60kDa in size and comprise a long N-terminal extracellular domain, containing a putative signal peptide and a disulphide-bonded β structural loop; 4 putative transmembrane (TM) domains; and a large cytoplasmic loop connecting the third and fourth TM domains. Amongst family members, the large cytoplasmic loop displays the most divergence in terms of primary structure, the TM domains showing the highest level of sequence conservation
[6]
.

Most GABAA receptors contain one type of alpha and beta subunit, and a single gamma polypeptide in a ratio of 2:2:1
[2]
, though in some cases other subunits such as epsilon or delta may replace gamma. The BZ binding site is located at the interface of adjacent alpha and gamma subunits; therefore, the type of alpha and gamma subunits present is instrumental in determining BZ selectivity and sensitivity. Receptors can be categorised into 3 groups based on their alpha subunit content and, hence, sensitivity to BZs: alpha 1-containing receptors have greatest sensitivity towards BZs (type I); alpha 2, 3 and 5-containing receptors have similar but distinguishable properties (type II); and alpha 4-and 6-containing assemblies have very low BZ affinity
[2]
. A conserved histidine residue in the alpha subunit of type I and II receptors is believed to be responsible for BZ affinity
[2]
.

This entry also includes glycine receptor subunit alpha
[8]
; subunits of the acetylcholine-gated chloride channel (ACC), Acetylcholine-gated ion channel acc-4 and Serotonin-gated chloride channel mod-1 in the nematode Caenorhabditis elegans; and Glutamate-gated chloride channel from Drosophila melanogaster (DrosGluCl). ACC is a heteropentamer consisting of ACC-1 and ACC-3, ACC-1 and ACC-4, ACC-2 and ACC-3 or ACC-2 and ACC-4. It is triggered in response to acetylcholine, but not GABA, glutamate, glycine, histamine or dopamine
[1]
. DrosGluCl plays an important role in the visual response by regulating the activity of ON/OFF-selective neurons
[9]
.

References

1.A family of acetylcholine-gated chloride channel subunits in Caenorhabditis elegans. Putrenko I, Zakikhani M, Dent JA. J. Biol. Chem. 280, 6392-8, (2005). View articlePMID: 15579462

2.GABA(A)-receptor subtypes: a new pharmacology. Mohler H, Crestani F, Rudolph U. 1, 22-5, (2001). View articlePMID: 11712530

3.International Union of Pharmacology. XV. Subtypes of gamma-aminobutyric acidA receptors: classification on the basis of subunit structure and receptor function. Barnard EA, Skolnick P, Olsen RW, Mohler H, Sieghart W, Biggio G, Braestrup C, Bateson AN, Langer SZ. Pharmacol. Rev. 50, 291-313, (1998). View articlePMID: 9647870

4.Structure and pharmacology of vertebrate GABAA receptor subtypes. Whiting PJ, McKernan RM, Wafford KA. Int. Rev. Neurobiol. 38, 95-138, (1995). PMID: 8537206

5.theta, a novel gamma-aminobutyric acid type A receptor subunit. Bonnert TP, McKernan RM, Farrar S, le Bourdelles B, Heavens RP, Smith DW, Hewson L, Rigby MR, Sirinathsinghji DJ, Brown N, Wafford KA, Whiting PJ. Proc. Natl. Acad. Sci. U.S.A. 96, 9891-6, (1999). View articlePMID: 10449790

6.Importance of a novel GABAA receptor subunit for benzodiazepine pharmacology. Pritchett DB, Sontheimer H, Shivers BD, Ymer S, Kettenmann H, Schofield PR, Seeburg PH. Nature 338, 582-5, (1989). View articlePMID: 2538761

7.GABA(A) receptor subtypes: dissecting their pharmacological functions. Rudolph U, Crestani F, Mohler H. Trends Pharmacol. Sci. 22, 188-94, (2001). View articlePMID: 11282419

8.Inhibitory glycine receptors: an update. Dutertre S, Becker CM, Betz H. J. Biol. Chem. 287, 40216-23, (2012). View articlePMID: 23038260

9.ON selectivity in the <i>Drosophila</i> visual system is a multisynaptic process involving both glutamatergic and GABAergic inhibition. Molina-Obando S, Vargas-Fique JF, Henning M, Gur B, Schladt TM, Akhtar J, Berger TK, Silies M. Elife 8, (2019). PMID: 31535971

GO terms

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