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PR01622

Identifier
GABAARGAMMA2  [View Relations]  [View Alignment]  
Accession
PR01622
No. of Motifs
3
Creation Date
05-DEC-2001
Title
Gamma-aminobutyric-acid A receptor gamma 2 subunit signature
Database References
PRINTS; PR00252 NRIONCHANNEL; PR00253 GABAARECEPTR; PR01620 GABAARGAMMA

MIM; 137164
Literature References
1. WHITING, P.J., MCKERNAN, R.M. AND WAFFORD, K.A.
Structure and pharmacology of vertebrate GABA(A) receptor subtypes.
INT.REV.NEUROBIOL. 38 95-138 (1995).
 
2. ASHCROFT, F.M.
GABA(A) Receptors.
IN ION CHANNELS AND DISEASE, ACADEMIC PRESS, 2000, PP.325-336.
 
3. RUDOLPH, U., CRESTANI, F. AND MOHLER, H.
GABA(A) receptor subtypes: dissecting their pharmacological functions.
TRENDS PHARMACOL.SCI. 22 188-194 (2001).
 
4. BARNARD, E.A., SKOLNICK, P., OLSEN, R.W., MOHLER, H., SIEGHART, W., 
BIGGIO, G., BRAESTRUP, C., BATESON, A.N. AND LANGER, S.Z.
International Union of Pharmacology: XV. Subtypes of gamma-aminobutyric acid
function.
PHARMACOL.REV. 50 291-313 (1998).
 
5. BONNERT, T.P., MCKERNAN, R.M., FARRAR, S., LE BOURDELLES, B., HEAVENS, 
R.P., SMITH, D.W., HEWSON, L., RIGBY, M.R., SIRINATHSINGHJI, BROWN, N., 
WAFFORD, K.A. AND WHITING, P.J.
Theta, a novel gamma-aminobutyric acid type A receptor subunit.
PROC.NATL.ACAD.SCI.U.S.A. 96 9891-9896 (1999).
 
6. PRITCHETT, D.B., SONTHEIMER, H., SHIVERS, B.D., YMER, S., KETTENMANN, H.,
SCHOFIELD, P.R. AND SEEBERG, P.H.
Importance of a novel GABA(A) receptor subunit for benzodiazepine 
pharmacology.
NATURE 338 582-585 (1989).
 
7. MOHLER, H., CRESTANI, F. AND RUDOLPH, U.
GABA(A)-receptor subtypes: a new pharmacology.
CURR.OPIN.PHARMACOL. 1 22-25 (2001).
 
8. HERB, A., WISDEN, W., LUDDENS, H., PUIA, G., VICINI, S. AND SEEBERG, P.H.
The third gamma subunit of the gamma-aminobutyric acid type A receptor 
family.
PROC.NATL.ACAD.SCI.U.S.A. 89 1433-1437 (1992).

Documentation
Gamma-aminobutyric acid type A (GABAA) receptors are members of the neuro-
transmitter 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) [1,2]. 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 [1].
 
GABAA receptors are pentameric membrane proteins that operate GABA-gated
chloride channels [3]. 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 [4,5]. Subunits are typically 50-60kDa
in size and comprise a long N-terminal extracellular domain, containing
a putative signal peptide and a disulphide-bonded beta structural loop; 4
putative transmembrane (TM) domains; and a large cytoplasmic loop connecting
the third and fourth TM domains [2]. 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].
 
Immunoprecipitation studies have shown that most GABAA receptors contain one
type of alpha and beta subunit, and a single gamma polypeptide in a ratio of
2:2:1 [1]. Whilst the critical residue involved in BZ binding is believed to
be located within the alpha subunit [7], the BZ binding site is considered
to be located at the interface between adjacent alpha and gamma subunits:
replacement of gamma subunits with delta and epsilon renders the receptor
insensitive to BZs due to disruption of the binding site [4]. Three
mammalian gamma subunits have been identified (gamma 1 to 3), each encoded
by a separate gene, plus an avian gamma 4 subunit. 
 
The presence of a gamma 2 subunit, together with alpha 1, confers 
`classical' BZ-binding activity to GABAA receptors; substitution for
gamma 1 or 3 leads to an altered binding profile for BZs [4]. The gamma 2 
gene undergoes alternative exon splicing leading to the generation of two
isoforms that differ by an additional 24-bp exon in the large putative
cytoplasmic domain [3]. The isoforms are termed gamma 2L (long) and gamma
2S (short), and are ubiquitously expressed. The gamma 2L splice variant has
been implicated in potentiation of GABAA receptors by ethanol.
 
GABAARGAMMA2 is a 3-element fingerprint that provides a signature for GABAA
gamma 2 subunits. The fingerprint was derived from an initial alignment of 5
sequences: the motifs were drawn from conserved regions spanning virtually
the full alignment length, focusing on those sections that characterise
gamma 2 subunits but distinguish them from the rest of the GABAA receptor 
gamma subunit family - motifs 1 and 2 reside in the extracellular N-terminal
domain; and motif 3 lies in the cytoplasmic loop between TM domains 3 and 4
[8]. A single iteration on SPTR40_18f was required to reach convergence, no
further sequences being identified beyond the starting set.                     
Summary Information
5 codes involving  3 elements
0 codes involving 2 elements
Composite Feature Index
3555
2000
123
True Positives
GAC2_BOVIN    GAC2_CHICK    GAC2_HUMAN    GAC2_MOUSE    
GAC2_RAT
Sequence Titles
GAC2_BOVIN  Gamma-aminobutyric-acid receptor gamma-2 subunit precursor (GABA(A) receptor) - Bos taurus (Bovine). 
GAC2_CHICK Gamma-aminobutyric-acid receptor gamma-2 subunit precursor (GABA(A) receptor) - Gallus gallus (Chicken).
GAC2_HUMAN Gamma-aminobutyric-acid receptor gamma-2 subunit precursor (GABA(A) receptor) - Homo sapiens (Human).
GAC2_MOUSE Gamma-aminobutyric-acid receptor gamma-2 subunit precursor (GABA(A) receptor) - Mus musculus (Mouse).
GAC2_RAT Gamma-aminobutyric-acid receptor gamma-2 subunit precursor (GABA(A) receptor) - Rattus norvegicus (Rat).
Scan History
SPTR40_18f 1  300  NSINGLE    
Initial Motifs
Motif 1  width=15
Element Seqn Id St Int Rpt
MSSPNIWSTGSSVYS GAC2_HUMAN 1 1 -
MSSPNTWSTGSTVYS GAC2_RAT 1 1 -
MSSPNIWSTGSSVYS GAC2_BOVIN 1 1 -
MSSPNTWSIGSSVYS GAC2_MOUSE 1 1 -
MTPSNPTRLGSTALL GAC2_CHICK 1 1 -

Motif 2 width=22
Element Seqn Id St Int Rpt
PVFSQKMTVWILLLLSLYPGFT GAC2_HUMAN 17 1 -
PVFSQKMTLWILLLLSLYPGFT GAC2_RAT 16 0 -
PVFSQKMTLWILLLLSLYPGLT GAC2_BOVIN 17 1 -
PVFSQKMTLWILLLLSLYPGFT GAC2_MOUSE 16 0 -
PAFSLKMMVWALVFLSLIQCST GAC2_CHICK 17 1 -

Motif 3 width=14
Element Seqn Id St Int Rpt
APTIDIRPRSATIQ GAC2_HUMAN 377 338 -
APTIDIRPRSATIQ GAC2_RAT 376 338 -
APTIDIRPRSATIQ GAC2_BOVIN 385 346 -
APTIDIRPRSATIQ GAC2_MOUSE 384 346 -
APTIDIRPRSATIQ GAC2_CHICK 384 345 -
Final Motifs
Motif 1  width=15
Element Seqn Id St Int Rpt
MSSPNIWSTGSSVYS GAC2_HUMAN 1 1 -
MSSPNTWSTGSTVYS GAC2_RAT 1 1 -
MSSPNIWSTGSSVYS GAC2_BOVIN 1 1 -
MSSPNTWSIGSSVYS GAC2_MOUSE 1 1 -
MTPSNPTRLGSTALL GAC2_CHICK 1 1 -

Motif 2 width=22
Element Seqn Id St Int Rpt
PVFSQKMTVWILLLLSLYPGFT GAC2_HUMAN 17 1 -
PVFSQKMTLWILLLLSLYPGFT GAC2_RAT 16 0 -
PVFSQKMTLWILLLLSLYPGLT GAC2_BOVIN 17 1 -
PVFSQKMTLWILLLLSLYPGFT GAC2_MOUSE 16 0 -
PAFSLKMMVWALVFLSLIQCST GAC2_CHICK 17 1 -

Motif 3 width=14
Element Seqn Id St Int Rpt
APTIDIRPRSATIQ GAC2_HUMAN 377 338 -
APTIDIRPRSATIQ GAC2_RAT 376 338 -
APTIDIRPRSATIQ GAC2_BOVIN 385 346 -
APTIDIRPRSATIQ GAC2_MOUSE 384 346 -
APTIDIRPRSATIQ GAC2_CHICK 384 345 -