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PR01672

Identifier
GABAARRHO2  [View Relations]  [View Alignment]  
Accession
PR01672
No. of Motifs
3
Creation Date
13-MAR-2002
Title
Gamma-aminobutyric-acid A (GABAA) receptor rho 2 subunit signature
Database References
PRINTS; PR00252 NRIONCHANNEL; PR00253 GABAARECEPTR; PR01670 GABAARRHO

MIM; 137162
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. RUDOLPH, U., CRESTANI, F. AND MOHLER, H.
GABA(A) receptor subtypes: dissecting their pharmacological functions.
TRENDS PHARMACOL.SCI. 22 188-194 (2001).
 
3. 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).   
 
4. BONNERT, T.P., MCKERNAN, R.M., FARRAR, S., LE BOURDELLES, B.,
HEAVENS, R.P., SMITH, D.W., HEWSON, L., RIGBY, M.R., SIRINATHSINGHJI, D.J.,
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).
 
5. ASHCROFT, F.M.
GABA(A) receptors.
IN ION CHANNELS AND DISEASE, ACADEMIC PRESS, 2000, PP.325-336.
 
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. ZHANG, D., PAN, Z.H., AWOBULUYI, M. AND LIPTON, S.A.
Structure and function of GABA(C) receptors: a comparison of native versus 
recombinant receptors.
TRENDS PHARMACOL.SCI. 22(3) 121-132 (2001).
 
8. DREW, C.A., JOHNSTON, G.A. AND WEATHERBY, R.P.
Bicuculline-insensitive GABA receptors: studies on the binding of 
NEUROSCI.LETT. 52 317-321 (1984).

Documentation
Gamma-aminobutyric acid type (GABA) is the major inhibitory neurotransmitter
in the vertebrate central nervous system (CNS). It modulates inhibitory tone
by interacting with two classes of receptor: ionotropic type A (GABAA) and
metabotropic type B (GABAB) receptors [1]. GABAA receptors are pentameric
membrane proteins that operate GABA-gated chloride channels [2] and belong
to the ligand-gated ion channel superfamily [1]. 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 [3,4].
Subunits are typically 50-60kDa in size and comprise a long N-terminal
extracellular domain; 4 putative transmembrane (TM) domains; and a large 
cytoplasmic loop connecting the third and fourth TM domains [5]. 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].
 
The effects of GABA on GABAA receptors are modulated by a range of
therapeutically important drugs, including barbiturates, anaesthetics and
benzodiazepines (BZs), which include the widely prescribed drugs librium and
valium [1,5]. Furthermore, they are characterised by their sensitivity
towards a selective antagonist, bicuculline [7]. A second type of ionotropic
GABA receptor has been identified that is insensitive to bicuculline and
classical GABAA modulators but has an enhanced affinity for GABA. This
receptor was found to be composed principally of rho subunits and was termed
'GABAC' in recognition of its altered pharmacology [8]. Despite this
distinction, rho subunits are generally considered to be part of the GABAA
family of receptor proteins due to similarities in sequence and topology.
 
Whilst early studies supported the view that rho subunits assembled to form
a homopentamer, it has been shown that a mutant rho 1 protein is able to
coassemble with GABAA gamma 2 subunits as well as the glycine receptor alpha
subunit [7]. Rho subunit mRNA occurs prominently in both human and rat
retina [3], each subunit showing a characteristic pattern of spatial
expression. In rat retina, rho 1 mRNA has been detected only in bipolar
cells, whereas rho 2 transcripts have been detected in both bipolar and
ganglion cells. In retinal tissues, expression of rho 3 mRNA is exclusive to
ganglion cells [7]. Reverse transcriptase PCR (RT-PCR) and in situ
hybridisation have shown rho transcripts also to be present in other regions
of the brain, specifically those involved in visual signal processing, such
as the superior colliculus and visual cortex [7].
 
Rho 2 mRNA is the most abundant transcript in rat brain, although studies of
recombinant systems have shown it to be unable to form functional homomeric
receptors [7]. The gene encoding the rho 2 subunit is located on chromosome
six, together with the gene for rho 1.
 
GABAARRHO2 is a 3-element fingerprint that provides a signature for GABAA
receptor rho 2 subunits. The fingerprint was derived from an initial
alignment of 4 sequences: the motifs were drawn from conserved regions
spanning the full alignment length, focusing on those sections that
characterise rho 2 subunits but distinguish them from the rest of the GABAA
receptor rho subunit family - motif 1 resides within the N-terminal domain;
and motifs 2 and 3 lie in the long cytoplasmic loop connecting TM domains 3
and 4 [7]. A single iteration on SPTR40_18f was required to reach
convergence, no further sequences being identified beyond the starting set.
Summary Information
4 codes involving  3 elements
0 codes involving 2 elements
Composite Feature Index
3444
2000
123
True Positives
GAR2_HUMAN    GAR2_MOUSE    GAR2_RAT      Q9YGQ5        
Sequence Titles
GAR2_HUMAN  Gamma-aminobutyric-acid receptor rho-2 subunit precursor (GABA(A) receptor) - Homo sapiens (Human). 
GAR2_MOUSE Gamma-aminobutyric-acid receptor rho-2 subunit precursor (GABA(A) receptor) - Mus musculus (Mouse).
GAR2_RAT Gamma-aminobutyric-acid receptor rho-2 subunit precursor (GABA(A) receptor) - Rattus norvegicus (Rat).
Q9YGQ5 GAMMA-AMINOBUTYRIC-ACID RECEPTOR RHO-2A SUBUNIT PRECURSOR - Morone americana (White perch).
Scan History
SPTR40_18f 1  300  NSINGLE    
Initial Motifs
Motif 1  width=14
Element Seqn Id St Int Rpt
RRKRWTGHLETSKP GAR2_RAT 24 24 -
RRKRWTGLLDTSKP GAR2_MOUSE 24 24 -
KRKRWTGQVEMPKP GAR2_HUMAN 24 24 -
RVRRWTGTVETQKH Q9YGQ5 26 26 -

Motif 2 width=16
Element Seqn Id St Int Rpt
LAGYPRSHILPEEERQ GAR2_RAT 389 351 -
LAGYPTSHILPKEERP GAR2_MOUSE 389 351 -
LAGYPRSHILTEEERQ GAR2_HUMAN 389 351 -
LAGYTEEPMVPERSRK Q9YGQ5 398 358 -

Motif 3 width=14
Element Seqn Id St Int Rpt
NSELTSSRKKGLLK GAR2_RAT 414 9 -
NSELTSSKKKGLLK GAR2_MOUSE 414 9 -
SGEANAARKKGLLK GAR2_HUMAN 414 9 -
SSESTTTKKKKSLR Q9YGQ5 431 17 -
Final Motifs
Motif 1  width=14
Element Seqn Id St Int Rpt
RRKRWTGHLETSKP GAR2_RAT 24 24 -
RRKRWTGLLDTSKP GAR2_MOUSE 24 24 -
KRKRWTGQVEMPKP GAR2_HUMAN 24 24 -
RVRRWTGTVETQKH Q9YGQ5 26 26 -

Motif 2 width=16
Element Seqn Id St Int Rpt
LAGYPRSHILPEEERQ GAR2_RAT 389 351 -
LAGYPTSHILPKEERP GAR2_MOUSE 389 351 -
LAGYPRSHILTEEERQ GAR2_HUMAN 389 351 -
LAGYTEEPMVPERSRK Q9YGQ5 398 358 -

Motif 3 width=14
Element Seqn Id St Int Rpt
NSELTSSRKKGLLK GAR2_RAT 414 9 -
NSELTSSKKKGLLK GAR2_MOUSE 414 9 -
SGEANAARKKGLLK GAR2_HUMAN 414 9 -
SSESTTTKKKKSLR Q9YGQ5 431 17 -