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PR01618

Identifier
GABAARALPHA5  [View Relations]  [View Alignment]  
Accession
PR01618
No. of Motifs
4
Creation Date
05-DEC-2001
Title
Gamma-aminobutyric-acid A receptor alpha 5 subunit signature
Database References
PRINTS; PR00252 NRIONCHANNEL; PR00253 GABAARECEPTR; PR01079 GABAARALPHA

MIM; 137142
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. SCHWARTZKROIN, P.A.
GABA synapses enter the molecular big time.
NAT.MED. 4 1115-1116 (1998).
 
9. 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]. The BZ binding site is located at the interface of adjacent alpha
and gamma subunits; therefore, the type of alpha subunit 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 [1]. A conserved histidine residue in
the alpha subunit of type I and II receptors is believed to be responsible
for BZ affinity [7]. It is becoming clear that GABAA receptors represent an
important point of therapuetic intervention in some neurological disorders.
For example, a predominance of type II over type I receptors in hippocampal
dentate granule cells, together with receptor density at the synapse, has 
been linked to epilepsy [8].
 
Amongst type II members, alpha 5-containing receptors exhibit an altered BZ
selectivity. Affinity towards the compound zolpidem distinguishes alpha 5
from alpha 2- and alpha 3-containing receptor subtypes [1]. The alpha 5
subunit is expressed primarily in the hippocampus.
 
GABAARALPHA5 is a 4-element fingerprint that provides a signature for GABAA
receptor alpha 5 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 alpha 5 subunits but distinguish them from the rest of the 
GABAA receptor alpha subunit family - motifs 1 and 2 lie in the N-terminal
region of the long extracellular loop preceding TM domain 1; motif 3 resides
in the cytoplasmic loop between TM domains 3 and 4; and motif 4 spans the
C-terminal region of TM domain 4 [9], leading into the C-terminus. A 
single iteration on SPTR40_18f 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
GAA5_HUMAN    GAA5_RAT      
Sequence Titles
GAA5_HUMAN  Gamma-aminobutyric-acid receptor alpha-5 subunit precurso (GABA(A) receptor) - Homo sapiens (Human). 
GAA5_RAT Gamma-aminobutyric-acid receptor alpha-5 subunit precurso (GABA(A) receptor) - Rattus norvegicus (Rat).
Scan History
SPTR40_18f 1  300  NSINGLE    
Initial Motifs
Motif 1  width=13
Element Seqn Id St Int Rpt
MDNGMFSGFIMIK GAA5_HUMAN 1 1 -
MDNGMLSRFIMTK GAA5_RAT 1 1 -

Motif 2 width=15
Element Seqn Id St Int Rpt
FCISMNLSSHFGFSQ GAA5_HUMAN 18 4 -
FCISMTLSSHFGFSQ GAA5_RAT 18 4 -

Motif 3 width=22
Element Seqn Id St Int Rpt
TGKMSHPPNIPKEQTPAGTSNT GAA5_HUMAN 379 346 -
TGKLTHPPNIPKEQLPGGTGNA GAA5_RAT 380 347 -

Motif 4 width=11
Element Seqn Id St Int Rpt
REPVIKGAASP GAA5_HUMAN 451 50 -
REPVIKGATSP GAA5_RAT 453 51 -
Final Motifs
Motif 1  width=13
Element Seqn Id St Int Rpt
MDNGMFSGFIMIK GAA5_HUMAN 1 1 -
MDNGMLSRFIMTK GAA5_RAT 1 1 -

Motif 2 width=15
Element Seqn Id St Int Rpt
FCISMNLSSHFGFSQ GAA5_HUMAN 18 4 -
FCISMTLSSHFGFSQ GAA5_RAT 18 4 -

Motif 3 width=22
Element Seqn Id St Int Rpt
TGKMSHPPNIPKEQTPAGTSNT GAA5_HUMAN 379 346 -
TGKLTHPPNIPKEQLPGGTGNA GAA5_RAT 380 347 -

Motif 4 width=11
Element Seqn Id St Int Rpt
REPVIKGAASP GAA5_HUMAN 451 50 -
REPVIKGATSP GAA5_RAT 453 51 -