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PR01724

Identifier
GABAARPI  [View Relations]  [View Alignment]  
Accession
PR01724
No. of Motifs
4
Creation Date
07-JUN-2002
Title
Gamma-aminobutyric-acid A receptor pi subunit signature
Database References
PRINTS; PR00252 NRIONCHANNEL; PR00253 GABAARECEPTR
MIM; 602729
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. HEDBLOM, E. AND KIRKNESS, E.F.
A novel class of GABA(A) receptor subunit in tissues of the reproductive 
system.
J.BIOL.CHEM. 272 15346-15350 (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 existence of a pi subunit was first reported in 1997, where it was
detected in a number of human and rat tissues. The subunit shares 30-40%
amino acid identity with other members of the GABAA receptor subunit family.
The polypeptide is found in several peripheral tissues, including the
uterus, where its function appears to be related to tissue contractility: pi
subunits can co-assemble with other GABAA receptor subunits to form
recombinant receptors with altered sensitivity to pregnenalone [7].   
 
GABAARPI is a 4-element fingerprint that provides a signature for GABAA
receptor pi 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 pi 
subunits but distinguish them from the rest of the GABAA receptor subunit 
family - motifs 1-3 reside within the presumed extracellular N-terminal 
region, motif 1 encoding the putative signal peptide; and motif 4 lies in
the large cytoplasmic loop between TM domains 3 and 4. A single iteration
on SPTR40_20f was required to reach convergence, no further sequences being
identified beyond the starting set.
Summary Information
2 codes involving  4 elements
0 codes involving 3 elements
0 codes involving 2 elements
Composite Feature Index
42222
30000
20000
1234
True Positives
GAAP_HUMAN    GAAP_RAT      
Sequence Titles
GAAP_HUMAN  Gamma-aminobutyric-acid receptor pi subunit precursor (GABA(A) receptor) - Homo sapiens (Human). 
GAAP_RAT Gamma-aminobutyric-acid receptor pi subunit precursor (GABA(A) receptor) - Rattus norvegicus (Rat).
Scan History
SPTR40_18f 1  300  NSINGLE    
Initial Motifs
Motif 1  width=25
Element Seqn Id St Int Rpt
MNYSLHLAFVCLSLFTERMCIQGSQ GAAP_HUMAN 1 1 -
MSYSLYLAFVCLNLLAQRMCIQGNQ GAAP_RAT 1 1 -

Motif 2 width=22
Element Seqn Id St Int Rpt
FNVEVGRSDKLSLPGFENLTAG GAAP_HUMAN 26 0 -
FNVEVSRSDKLSLPGFENLTAG GAAP_RAT 26 0 -

Motif 3 width=22
Element Seqn Id St Int Rpt
SSISESNMDYTATIYLRQRWMD GAAP_HUMAN 73 25 -
SSISESNMDYTATIYLRQRWTD GAAP_RAT 73 25 -

Motif 4 width=15
Element Seqn Id St Int Rpt
KTSDKFKFVFREKMG GAAP_HUMAN 386 291 -
KASDKFKFVFREKIG GAAP_RAT 386 291 -
Final Motifs
Motif 1  width=25
Element Seqn Id St Int Rpt
MNYSLHLAFVCLSLFTERMCIQGSQ GAAP_HUMAN 1 1 -
MSYSLYLAFVCLNLLAQRMCIQGNQ GAAP_RAT 1 1 -

Motif 2 width=22
Element Seqn Id St Int Rpt
FNVEVGRSDKLSLPGFENLTAG GAAP_HUMAN 26 0 -
FNVEVSRSDKLSLPGFENLTAG GAAP_RAT 26 0 -

Motif 3 width=22
Element Seqn Id St Int Rpt
SSISESNMDYTATIYLRQRWMD GAAP_HUMAN 73 25 -
SSISESNMDYTATIYLRQRWTD GAAP_RAT 73 25 -

Motif 4 width=15
Element Seqn Id St Int Rpt
KTSDKFKFVFREKMG GAAP_HUMAN 386 291 -
KASDKFKFVFREKIG GAAP_RAT 386 291 -