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PR01723

Identifier
GABAAREPSLON  [View Relations]  [View Alignment]  
Accession
PR01723
No. of Motifs
3
Creation Date
07-JUN-2002
Title
Gamma-aminobutyric-acid A receptor epsilon subunit signature 
Database References
PRINTS; PR00252 NRIONCHANNEL; PR00253 GABAARECEPTR
MIM; 300093
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. DAVIES, P.A., HANNA, M.C., HALES, T.G. AND KIRKNESS, E.F.
Insensitivity to anaesthetic agents conferred by a class of GABA(A) 
receptor subunit.   
NATURE 385 820-823 (1997).

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].
 
Evidence suggests that the structure of GABAA receptors is analagous to that
of the nicotinic acetylcholine receptor, namely a pentameric protein with
the ion channel located in the centre of a rosette formed between five 
homologous subunits [4]. The majority of receptors contain one type of alpha
and beta subunit, and a single gamma polypeptide in a ratio of 2:2:1 [1].
 
The epsilon subunit was first identified in 1997 using a combination of
bioinformatics-based and traditional molecular biology approaches to
identify a full-length cDNA [7]. Northern blot analysis of several human
brain tissues showed that epsilon transcripts were relatively enriched in
amygdala and thalamus, compared to whole brain, and particularly abundant in
the subthalmic nucleus. Heteromeric recombinant receptors containing the
epsilon subunit were found to be insenstitive to the potentiating effects of
anaesthetic agents.    
 
GABAAREPSLON is a 3-element fingerprint that provides a signature for GABAA
receptor epsilon subunits. The fingerprint was derived from an initial
alignment of 2 sequences: the motifs were drawn from conserved regions
spanning the full alignment length, focusing on those sections that
characterise epsilon subunits but distinguish them from the rest of the 
GABAA receptor subunit family - the motifs all reside within the large
cytoplasmic loop between TM domains 3 and 4. Two iterations on SPTR40_20f
were required to reach convergence, at which point a true set comprising 6
sequences was identified.
Summary Information
6 codes involving  3 elements
0 codes involving 2 elements
Composite Feature Index
3666
2000
123
True Positives
GAE_HUMAN     GAE_RAT       Q9JLE7        Q9JLE8        
Q9JLE9 Q9QY43
Sequence Titles
GAE_HUMAN   Gamma-aminobutyric-acid receptor epsilon subunit precursor (GABA(A) receptor) - Homo sapiens (Human). 
GAE_RAT Gamma-aminobutyric-acid receptor epsilon subunit precursor (GABA(A) receptor) - Rattus norvegicus (Rat).
Q9JLE7 GABA-A RECEPTOR EPSILON-LIKE SUBUNIT - Mus musculus (Mouse).
Q9JLE8 GABA-A RECEPTOR EPSILON-LIKE SUBUNIT - Mus musculus (Mouse).
Q9JLE9 GABA-A RECEPTOR EPSILON-LIKE SUBUNIT - Rattus norvegicus (Rat).
Q9QY43 GABA RECEPTOR EPSILON SUBUNIT - Mus musculus (Mouse).
Scan History
SPTR40_20f 2  300  NSINGLE    
Initial Motifs
Motif 1  width=17
Element Seqn Id St Int Rpt
NIERQASPKFYQFPTNS GAE_RAT 369 369 -
QTKAHASPKLRHPRINS GAE_HUMAN 368 368 -

Motif 2 width=20
Element Seqn Id St Int Rpt
QQQEVFVCEIVTYEENAEEG GAE_RAT 407 21 -
QHQEAFVCQIVTTEGSDGEE GAE_HUMAN 400 15 -

Motif 3 width=23
Element Seqn Id St Int Rpt
YQWSPRSRRPQCPWRRCGRSYVC GAE_RAT 427 0 -
AQQPPSPGSPEGPRSLCSKLACC GAE_HUMAN 425 5 -
Final Motifs
Motif 1  width=17
Element Seqn Id St Int Rpt
NIKRQASLKVYQLPTNS Q9JLE7 775 775 -
NIKRQASLKVYQLPTNS Q9QY43 359 359 -
NIKRQASLKVYQLPTNS Q9JLE8 773 773 -
NIERQASPKFYQFPTNS GAE_RAT 369 369 -
NIERQASPKFYQFPTNS Q9JLE9 852 852 -
QTKAHASPKLRHPRINS GAE_HUMAN 368 368 -

Motif 2 width=20
Element Seqn Id St Int Rpt
QQQEVFVCEIVTYEENAEEG Q9JLE7 813 21 -
QQQEVFVCEIVTYEENAEEG Q9QY43 397 21 -
QQQEVFVCEIVTYEENAEEG Q9JLE8 811 21 -
QQQEVFVCEIVTYEENAEEG GAE_RAT 407 21 -
QQQEVFVCEIVTYEENAEEG Q9JLE9 890 21 -
QHQEAFVCQIVTTEGSDGEE GAE_HUMAN 400 15 -

Motif 3 width=23
Element Seqn Id St Int Rpt
YQWSPRSRRPQCPWRRCGRSYVC Q9JLE7 833 0 -
YQWSPRSRRPQCPWRRCGRSYVC Q9QY43 417 0 -
YQWSPRSRRPQCPWRRCGRSYVC Q9JLE8 831 0 -
YQWSPRSRRPQCPWRRCGRSYVC GAE_RAT 427 0 -
YQWSPRSRRPQCPWRRCGRSYVC Q9JLE9 910 0 -
AQQPPSPGSPEGPRSLCSKLACC GAE_HUMAN 425 5 -