| Literature References | 1. KOFUJI, P., WANG, J.B., MOSS, S.J., HUGANIR, R.L. AND BURT, D.R.
Generation of two forms of the gamma-aminobutyric acid A receptor gamma
2-subunit in mice by alternative splicing.
J.NEUROCHEM. 56 713-715 (1991).
2. WANG, J.B., KOFUJI, P., FERNANDO, J.C., MOSS, S.J., HUGANIR, R.L.
AND BURT, D.R.
The alpha 1, alpha 2, and alpha 3 subunits of GABAA receptors: comparison
in seizure-prone and -resistant mice and during development.
J.MOL.NEUROSCIENCE 3 177-184 (1992).
3. LEVITAN, E.S., SCHOFIELD, P.R., BURT, D.R., RHEE, L.M., WISDEN, W.,
KOHLER, M., FUJITA, N., RODRIGUEZ, H.F., STEPHENSON, A., DARLISON, M.G.,
BARNARD, E.A. AND SEEBURG, P.H.
Structural and functional basis for GABAA receptor heterogeneity.
NATURE 335 76-79 (1988).
4. KHRESTCHATISKY, M., MACLENNAN, A.J., TILLAKARATNE, N.J., CHIANG, M.Y.
AND TOBIN, A.J.
Sequence and regional distribution of the mRNA encoding the alpha 2
polypeptide of rat gamma-aminobutyric acid A receptors.
J.NEUROCHEM. 56 1717-1722 (1991).
5. THOMPSON, M., SHOTKOSKI, F. AND FFRENCH-CONSTANT, R.
Cloning and sequencing of the cyclodiene insecticide resistance gene from
the yellow fever mosquito Aedes aegypti. Conservation of the gene and
resistance associated mutation with Drosophila.
FEBS LETT. 325(3) 187-90 (1993).
6. SIGEL, E., BAUR, R., KELLENBERGER, S. AND MALHERBE, P.
Point mutations affecting antagonist affinity and agonist dependent gating
of GABAA receptor channels.
EMBO J. 11 2017-2023 (1992).
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| Documentation | Gamma-aminobutyric acid (GABA) receptors are members of the neurotransmitter
ligand-gated ion channels: they mediate neuronal inhibition by opening
chloride channels on binding GABA [1,2]. There are 5 classes of receptor
subunit (alpha, beta, gamma, delta and rho), with variants in each class
[3]. Each subunit contains 4 proposed transmembrane (TM) domains, with a
large intracellular loop between the third and fourth domain. Active
receptors contain 5 subunits of varying classes and variants - the use
of highly similar receptor subtypes, which differ in functionality, is a
common feature of brain receptors [3].
The neurotransmitter action of the subtype A receptor (GABAA) is
potentiated by both benzodiazepines and barbiturates [3]. Alpha subunits
largely determine benzodiazepine binding properties [4], and gamma-2
subunits appear to be essential for benzodiazepine modulation of receptor
function [1]. In insects, cyclodiene (an insecticide) resistence is due to
insensitivity of the cyclodiene/picrotoxinin binding site on the GABAA
receptor-chloride ionophore complex [5].
Mutagenesis and agonist/antagonist binding studies have suggested a close
functional and structural association of alpha-subunits with the agonist/
antagonist binding site, and involvement of N-terminal portions of the
extracellular domains of all subunits in the gating of the channel [6].
GABAARALPHA is an 8-element fingerprint that provides a signature for GABAA
alpha subunit precursors. The fingerprint was derived from an initial
alignment of 12 sequences: the motifs were drawn from short conserved
regions spanning virtually the full alignment length, focusing on those
sections that characterise the alpha subunits but distinguish them from
the rest of the GABA receptor superfamily - motifs 1-5 lie withing the
N-terminal extracellular domain; motif 6 spans part of the extracellular
loop and the N-terminus of putative TM domain 3; and motifs 7 and 8 span
the cytoplasmic loop and putative TM domain 4. Two iterations on OWL31.1
were required to reach convergence, at which point a true set comprising 24
sequences was identified. Several partial matches were also found: HSGABAA
and MMAJ2970 and fragments that lack portions of sequence bearing the
C-terminal motifs; and GAC3_HUMAN, GAC3_MOUSE and GAC3_RAT are GABA
receptor gamma subunit precursors.
An update on SPTR37_9f identified a true set of 22 sequences, and 3
partial matches.
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