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PR01620

Identifier
GABAARGAMMA  [View Relations]  [View Alignment]  
Accession
PR01620
No. of Motifs
5
Creation Date
05-DEC-2001
Title
Gamma-aminobutyric-acid A receptor gamma subunit signature
Database References
PRINTS; PR00252 NRIONCHANNEL; PR00253 GABAARECEPTR; PR01621 GABAARGAMMA1
PRINTS; PR01622 GABAARGAMMA2; PR01623 GABAARGAMMA3
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].   
 
GABAARGAMMA is a 5-element fingerprint that provides a signature for GABAA
gamma subunits. The fingerprint was derived from an initial alignment of 11
sequences: the motifs were drawn from conserved regions spanning virtually
the full alignment length, focusing on those sections that characterise
gamma subunits but distinguish them from the rest of the GABAA receptor 
subunit family - motifs 1-3 lie in the long extracellular N-terminal domain;
motif 4 spans the C-terminal portion of TM domain 3, leading into the 
cytoplasmic loop; and motif 5 resides 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
11 codes involving  5 elements
0 codes involving 4 elements
0 codes involving 3 elements
0 codes involving 2 elements
Composite Feature Index
51111111111
400000
300000
200000
12345
True Positives
GAC1_MOUSE    GAC1_RAT      GAC2_BOVIN    GAC2_CHICK    
GAC2_HUMAN GAC2_MOUSE GAC2_RAT GAC3_HUMAN
GAC3_MOUSE GAC3_RAT GAC4_CHICK
Sequence Titles
GAC1_MOUSE  Gamma-aminobutyric-acid receptor gamma-1 subunit precursor (GABA(A) receptor) - Mus musculus (Mouse). 
GAC1_RAT Gamma-aminobutyric-acid receptor gamma-1 subunit precursor (GABA(A) receptor) - Rattus norvegicus (Rat).
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).
GAC3_HUMAN Gamma-aminobutyric-acid receptor gamma-3 subunit precursor (GABA(A) receptor) - Homo sapiens (Human).
GAC3_MOUSE Gamma-aminobutyric-acid receptor gamma-3 subunit precursor (GABA(A) receptor) - Mus musculus (Mouse).
GAC3_RAT Gamma-aminobutyric-acid receptor gamma-3 subunit precursor (GABA(A) receptor) - Rattus norvegicus (Rat).
GAC4_CHICK Gamma-aminobutyric-acid receptor gamma-4 subunit precursor (GABA(A) receptor) - Gallus gallus (Chicken).
Scan History
SPTR40_18f 1  150  NSINGLE    
Initial Motifs
Motif 1  width=12
Element Seqn Id St Int Rpt
LWILLLLSLYPG GAC2_BOVIN 25 25 -
LWILLLLSLYPG GAC2_RAT 24 24 -
LWILLLLSLYPG GAC2_MOUSE 24 24 -
VWILLLLSLYPG GAC2_HUMAN 25 25 -
VWALVFLSLIQC GAC2_CHICK 25 25 -
IFLLLTLHLGNC GAC1_RAT 24 24 -
LCLFSGLHARSR GAC3_RAT 9 9 -
LCLFSGLHARSR GAC3_HUMAN 9 9 -
LCLFSGLHARSR GAC3_MOUSE 9 9 -
IFLLLTLHLGNC GAC1_MOUSE 24 24 -
LCLALGPALRSA GAC4_CHICK 8 8 -

Motif 2 width=28
Element Seqn Id St Int Rpt
DDDYEDYASNKTWVLTPKVPEGDVTVIL GAC2_BOVIN 43 6 -
DDDYEDYASNKTWVLTPKVPEGDVTVIL GAC2_RAT 42 6 -
DDDYEDYTSNKTWVLTPKVPEGDVTVIL GAC2_MOUSE 42 6 -
DDDYEDYASNKTWVLTPKVPEGDVTVIL GAC2_HUMAN 43 6 -
DDDYEDYTSNKTWVLTPKVHESDVTLIL GAC2_CHICK 42 5 -
DEDDEDLTMNKTWVLAPKIHEGDITQIL GAC1_RAT 41 5 -
EDDSEDSPSNQKWVLAPKSQDTDVTLIL GAC3_RAT 24 3 -
EDEYEDSSSNQKWVLAPKSQDTDVTLIL GAC3_HUMAN 24 3 -
EDENEDSPSNQKWVLAPKPQDTDATLIL GAC3_MOUSE 24 3 -
DEDDEDLTMNKTWVLAPKIHEGDITQIL GAC1_MOUSE 41 5 -
EYDYDYLSINKTWVLTPKAQETDATQIL GAC4_CHICK 26 6 -

Motif 3 width=27
Element Seqn Id St Int Rpt
NLLEGYDNKLRPDIGVKPTLIHTDMYV GAC2_BOVIN 72 1 -
NLLEGYDNKLRPDIGVKPTLIHTDMYV GAC2_RAT 71 1 -
NLLEGYDNKLRPDIGVKPTLIHTDMYV GAC2_MOUSE 71 1 -
NLLEGYDNKLRPDIGVKPTLIHTDMYV GAC2_HUMAN 72 1 -
GLLEGYDNKLRPDIGVKPTVIHTDMYV GAC2_CHICK 71 1 -
SLLQGYDNKLRPDIGVRPTVIETDVYV GAC1_RAT 70 1 -
KLLREYDKKLRPDIGIKPTVIDVDIYV GAC3_RAT 53 1 -
KLLREYDKKLRPDIGIKPTVIDVDIYV GAC3_HUMAN 53 1 -
KLLREYDKKLRPDIGIKPTVIDVDIYV GAC3_MOUSE 53 1 -
SLLQGYDNKLRPDIGVRPTVIETDVYV GAC1_MOUSE 70 1 -
SLLKNYDNKLRPDIGIKPTFIDVDIYV GAC4_CHICK 55 1 -

Motif 4 width=23
Element Seqn Id St Int Rpt
LVEYGTLHYFVSNRKPSKDKDKK GAC2_BOVIN 350 251 -
LVEYGTLHYFVSNRKPSKDKDKK GAC2_RAT 349 251 -
LVEYGTLHYFVSNRKPSKDKDKK GAC2_MOUSE 349 251 -
LVEYGTLHYFVSNRKPSKDKDKK GAC2_HUMAN 350 251 -
LVEYGTLHYFVSNRKPSKDKDKK GAC2_CHICK 349 251 -
LMEYGTLHYFTSNNKGKTTRDRK GAC1_RAT 348 251 -
LMEYATLNYYSSCRKPTIRKKKT GAC3_RAT 331 251 -
LMEYATLNYYSSCRKPTTTKKTT GAC3_HUMAN 331 251 -
LMEYATLNYYSSCRKPTIRKKKT GAC3_MOUSE 331 251 -
LMEYGTLHYFTSNNKGKTTRGRK GAC1_MOUSE 348 251 -
LMEYATLNYLVGNKKPLEHSSRK GAC4_CHICK 333 251 -

Motif 5 width=20
Element Seqn Id St Int Rpt
GYECLDGKDCASFFCCFEDC GAC2_BOVIN 413 40 -
GYECLDGKDCASFFCCFEDC GAC2_RAT 404 32 -
GYQCLDGKDCASFFCCFEDC GAC2_MOUSE 412 40 -
GYECLDGKDCASFFCCFEDC GAC2_HUMAN 405 32 -
GYECLDGKDCASFFCCFEDC GAC2_CHICK 412 40 -
GYQCLEGKDCATFFCCFEDC GAC1_RAT 403 32 -
VYECLDGKDCQSFFCCYEEC GAC3_RAT 405 51 -
VYECLDGKDCQSFFCCYEEC GAC3_HUMAN 405 51 -
VYECLDGKDCQSFFCCYEEC GAC3_MOUSE 405 51 -
GYQCLEGKDCTSFFCCFDRL GAC1_MOUSE 403 32 -
GSPCLEGKECERFFCCIEDC GAC4_CHICK 395 39 -
Final Motifs
Motif 1  width=12
Element Seqn Id St Int Rpt
LWILLLLSLYPG GAC2_BOVIN 25 25 -
LWILLLLSLYPG GAC2_RAT 24 24 -
LWILLLLSLYPG GAC2_MOUSE 24 24 -
VWILLLLSLYPG GAC2_HUMAN 25 25 -
VWALVFLSLIQC GAC2_CHICK 25 25 -
IFLLLTLHLGNC GAC1_RAT 24 24 -
LCLFSGLHARSR GAC3_RAT 9 9 -
LCLFSGLHARSR GAC3_HUMAN 9 9 -
LCLFSGLHARSR GAC3_MOUSE 9 9 -
IFLLLTLHLGNC GAC1_MOUSE 24 24 -
LCLALGPALRSA GAC4_CHICK 8 8 -

Motif 2 width=28
Element Seqn Id St Int Rpt
DDDYEDYASNKTWVLTPKVPEGDVTVIL GAC2_BOVIN 43 6 -
DDDYEDYASNKTWVLTPKVPEGDVTVIL GAC2_RAT 42 6 -
DDDYEDYTSNKTWVLTPKVPEGDVTVIL GAC2_MOUSE 42 6 -
DDDYEDYASNKTWVLTPKVPEGDVTVIL GAC2_HUMAN 43 6 -
DDDYEDYTSNKTWVLTPKVHESDVTLIL GAC2_CHICK 42 5 -
DEDDEDLTMNKTWVLAPKIHEGDITQIL GAC1_RAT 41 5 -
EDDSEDSPSNQKWVLAPKSQDTDVTLIL GAC3_RAT 24 3 -
EDEYEDSSSNQKWVLAPKSQDTDVTLIL GAC3_HUMAN 24 3 -
EDENEDSPSNQKWVLAPKPQDTDATLIL GAC3_MOUSE 24 3 -
DEDDEDLTMNKTWVLAPKIHEGDITQIL GAC1_MOUSE 41 5 -
EYDYDYLSINKTWVLTPKAQETDATQIL GAC4_CHICK 26 6 -

Motif 3 width=27
Element Seqn Id St Int Rpt
NLLEGYDNKLRPDIGVKPTLIHTDMYV GAC2_BOVIN 72 1 -
NLLEGYDNKLRPDIGVKPTLIHTDMYV GAC2_RAT 71 1 -
NLLEGYDNKLRPDIGVKPTLIHTDMYV GAC2_MOUSE 71 1 -
NLLEGYDNKLRPDIGVKPTLIHTDMYV GAC2_HUMAN 72 1 -
GLLEGYDNKLRPDIGVKPTVIHTDMYV GAC2_CHICK 71 1 -
SLLQGYDNKLRPDIGVRPTVIETDVYV GAC1_RAT 70 1 -
KLLREYDKKLRPDIGIKPTVIDVDIYV GAC3_RAT 53 1 -
KLLREYDKKLRPDIGIKPTVIDVDIYV GAC3_HUMAN 53 1 -
KLLREYDKKLRPDIGIKPTVIDVDIYV GAC3_MOUSE 53 1 -
SLLQGYDNKLRPDIGVRPTVIETDVYV GAC1_MOUSE 70 1 -
SLLKNYDNKLRPDIGIKPTFIDVDIYV GAC4_CHICK 55 1 -

Motif 4 width=23
Element Seqn Id St Int Rpt
LVEYGTLHYFVSNRKPSKDKDKK GAC2_BOVIN 350 251 -
LVEYGTLHYFVSNRKPSKDKDKK GAC2_RAT 349 251 -
LVEYGTLHYFVSNRKPSKDKDKK GAC2_MOUSE 349 251 -
LVEYGTLHYFVSNRKPSKDKDKK GAC2_HUMAN 350 251 -
LVEYGTLHYFVSNRKPSKDKDKK GAC2_CHICK 349 251 -
LMEYGTLHYFTSNNKGKTTRDRK GAC1_RAT 348 251 -
LMEYATLNYYSSCRKPTIRKKKT GAC3_RAT 331 251 -
LMEYATLNYYSSCRKPTTTKKTT GAC3_HUMAN 331 251 -
LMEYATLNYYSSCRKPTIRKKKT GAC3_MOUSE 331 251 -
LMEYGTLHYFTSNNKGKTTRGRK GAC1_MOUSE 348 251 -
LMEYATLNYLVGNKKPLEHSSRK GAC4_CHICK 333 251 -

Motif 5 width=20
Element Seqn Id St Int Rpt
GYECLDGKDCASFFCCFEDC GAC2_BOVIN 413 40 -
GYECLDGKDCASFFCCFEDC GAC2_RAT 404 32 -
GYQCLDGKDCASFFCCFEDC GAC2_MOUSE 412 40 -
GYECLDGKDCASFFCCFEDC GAC2_HUMAN 405 32 -
GYECLDGKDCASFFCCFEDC GAC2_CHICK 412 40 -
GYQCLEGKDCATFFCCFEDC GAC1_RAT 403 32 -
VYECLDGKDCQSFFCCYEEC GAC3_RAT 405 51 -
VYECLDGKDCQSFFCCYEEC GAC3_HUMAN 405 51 -
VYECLDGKDCQSFFCCYEEC GAC3_MOUSE 405 51 -
GYQCLEGKDCTSFFCCFDRL GAC1_MOUSE 403 32 -
GSPCLEGKECERFFCCIEDC GAC4_CHICK 395 39 -