Gamma-aminobutyric-acid A receptor, Rho (IPR008057)

Short name: GABAAa_rho_rcpt

Overlapping homologous superfamilies

Family relationships


Neurotransmitter ligand-gated ion channels are transmembrane receptor-ion channel complexes that open transiently upon binding of specific ligands, allowing rapid transmission of signals at chemical synapses [PMID: 1721053, PMID: 1846404]. Five of these ion channel receptor families have been shown to form a sequence-related superfamily:

  • Nicotinic acetylcholine receptor (AchR), an excitatory cation channel in vertebrates and invertebrates; in vertebrate motor endplates it is composed of alpha, beta, gamma and delta/epsilon subunits; in neurons it is composed of alpha and non-alpha (or beta) subunits [PMID: 18446614].
  • Glycine receptor, an inhibitory chloride ion channel composed of alpha and beta subunits [PMID: 15383648].
  • Gamma-aminobutyric acid (GABA) receptor, an inhibitory chloride ion channel; at least four types of subunits (alpha, beta, gamma and delta) are known [PMID: 18760291].
  • Serotonin 5HT3 receptor, of which there are seven major types (5HT3-5HT7) [PMID: 10026168].
  • Glutamate receptor, an excitatory cation channel of which at least three types have been described (kainate, N-methyl-D-aspartate (NMDA) and quisqualate) [PMID: 15165736].

These receptors possess a pentameric structure (made up of varying subunits), surrounding a central pore. All known sequences of subunits from neurotransmitter-gated ion-channels are structurally related. They are composed of a large extracellular glycosylated N-terminal ligand-binding domain, followed by three hydrophobic transmembrane regions which form the ionic channel, followed by an intracellular region of variable length. A fourth hydrophobic region is found at the C-terminal of the sequence [PMID: 1721053, PMID: 1846404].

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) [PMID: 8537206]. 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 [PMID: 11282419]. 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 [PMID: 9647870, PMID: 10449790]. Subunits are typically 50-60kDa in size and comprise a long N-terminal extracellular domain, containing a putative signal peptide and a disulphide-bonded beta 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 [PMID: 2538761].

Most GABAA receptors contain one type of alpha and beta subunit, and a single gamma polypeptide in a ratio of 2:2:1 [PMID: 11712530], 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 [PMID: 11712530]. A conserved histidine residue in the alpha subunit of type I and II receptors is believed to be responsible for BZ affinity [PMID: 11712530].

GABAA receptors can be characterised by their sensitivity towards a selective antagonist, bicuculline. A GABA receptor has been identified that is insensitive to bicuculline and classical GABAA modulators but has an enhanced affinity for GABA. This receptor, unlike most GABAA receptors, is composed principally of rho subunits and was initially termed 'GABAC' in recognition of its altered pharmacology [PMID: 6097844]. Despite these differences, rho subunits are generally considered to be part of the GABAA family of receptor proteins due to similarities in sequence and topology. Whilst early studies supported the view that rho subunits assembled to form a homopentamer, it has been shown that a mutant rho 1 protein is able to coassemble with GABAA gamma 2 subunits as well as the glycine receptor alpha subunit. Rho subunit mRNA occurs prominently in both human and rat retina [PMID: 9647870], each subunit showing a characteristic pattern of spatial expression. In rat retina, rho 1 mRNA has been detected only in bipolar cells, whereas rho 2 transcripts have been detected in both bipolar and ganglion cells. In retinal tissues, expression of rho 3 mRNA is exclusive to ganglion cells. Reverse transcriptase PCR (RT-PCR) and in situ hybridisation have shown rho transcripts also to be present in other regions of the brain, specifically those involved in visual signal processing, such as the superior colliculus and visual cortex.

This entry represents the GABAA Rho subunits.

GO terms

Biological Process

GO:0006811 ion transport

Molecular Function

GO:0004890 GABA-A receptor activity

Cellular Component

GO:0016020 membrane

Contributing signatures

Signatures from InterPro member databases are used to construct an entry.