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PR01670

Identifier
GABAARRHO  [View Relations]  [View Alignment]  
Accession
PR01670
No. of Motifs
3
Creation Date
13-MAR-2002
Title
Gamma-aminobutyric-acid A (GABAA) receptor rho subunit signature
Database References
PRINTS; PR00252 NRIONCHANNEL; PR00253 GABAARECEPTR; PR01671 GABAARRHO1
PRINTS; PR01672 GABAARRHO2
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].
 
GABAARRHO is a 3-element fingerprint that provides a signature for GABAA
receptor rho subunits. The fingerprint was derived from an initial alignment
of 9 sequences: the motifs were drawn from conserved regions spanning the
full alignment length, focusing on those sections that characterise rho
subunits but distinguish them from the rest of the GABAA receptor subunit
family - motif 1 lies at the N-terminus; and motifs 2 and 3 reside within
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
9 codes involving  3 elements
0 codes involving 2 elements
Composite Feature Index
3999
2000
123
True Positives
GAR1_HUMAN    GAR1_MOUSE    GAR1_RAT      GAR2_HUMAN    
GAR2_MOUSE GAR2_RAT GAR3_RAT O42157
Q9YGQ5
Sequence Titles
GAR1_HUMAN  Gamma-aminobutyric-acid receptor rho-1 subunit precursor (GABA(A) receptor) - Homo sapiens (Human). 
GAR1_MOUSE Gamma-aminobutyric-acid receptor rho-1 subunit precursor (GABA(A) receptor) - Mus musculus (Mouse).
GAR1_RAT Gamma-aminobutyric-acid receptor rho-1 subunit precursor (GABA(A) receptor) - Rattus norvegicus (Rat).
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).
GAR3_RAT Gamma-aminobutyric-acid receptor rho-3 subunit precursor (GABA(A) receptor) - Rattus norvegicus (Rat).
O42157 GABAC RECEPTOR SUBUNIT RHO-1B - Morone americana (White perch).
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=18
Element Seqn Id St Int Rpt
MPYLMRLALVLFCLMALV GAR2_MOUSE 1 1 -
MPYFMRLALFLFCLMALV GAR2_RAT 1 1 -
MKFGIFLLWWGWVLAAES GAR1_MOUSE 1 1 -
MKFGIFLLWWGWVLAAES GAR1_RAT 1 1 -
MRFGIFLLWWGWVLATES GAR1_HUMAN 1 1 -
MPYFTRLILFLFCLMVLV GAR2_HUMAN 1 1 -
MPCYVRFVLLLLCLVVIG O42157 1 1 -
MPYMTKPLILLLCLVVIG Q9YGQ5 1 1 -
MVLAFWLAFFTYTWITLM GAR3_RAT 1 1 -

Motif 2 width=12
Element Seqn Id St Int Rpt
MLDGSYSESEAN GAR2_MOUSE 376 357 -
TLDGSYSESEAN GAR2_RAT 376 357 -
MLDSSYSDGEVN GAR1_MOUSE 391 372 -
MLDSSYSDGEVN GAR1_RAT 391 372 -
MLDGNYSDGEVN GAR1_HUMAN 390 371 -
MLDGSYSESEAN GAR2_HUMAN 376 357 -
MLDGTYSEADAN O42157 386 367 -
MLDGTYSEADTN Q9YGQ5 385 366 -
AFDGCYHDGETD GAR3_RAT 379 360 -

Motif 3 width=11
Element Seqn Id St Int Rpt
SELTSSKKKGL GAR2_MOUSE 415 27 -
SELTSSRKKGL GAR2_RAT 415 27 -
SERGSPQRKGQ GAR1_MOUSE 426 23 -
SERGSPQRKSQ GAR1_RAT 426 23 -
SERSSPQRKSQ GAR1_HUMAN 425 23 -
GEANAARKKGL GAR2_HUMAN 415 27 -
NEPTGTKKKGI O42157 427 29 -
ESTTTKKKKSL Q9YGQ5 433 36 -
ADSSQIKRKSL GAR3_RAT 415 24 -
Final Motifs
Motif 1  width=18
Element Seqn Id St Int Rpt
MPYLMRLALVLFCLMALV GAR2_MOUSE 1 1 -
MPYFMRLALFLFCLMALV GAR2_RAT 1 1 -
MKFGIFLLWWGWVLAAES GAR1_MOUSE 1 1 -
MKFGIFLLWWGWVLAAES GAR1_RAT 1 1 -
MRFGIFLLWWGWVLATES GAR1_HUMAN 1 1 -
MPYFTRLILFLFCLMVLV GAR2_HUMAN 1 1 -
MPCYVRFVLLLLCLVVIG O42157 1 1 -
MPYMTKPLILLLCLVVIG Q9YGQ5 1 1 -
MVLAFWLAFFTYTWITLM GAR3_RAT 1 1 -

Motif 2 width=12
Element Seqn Id St Int Rpt
MLDGSYSESEAN GAR2_MOUSE 376 357 -
TLDGSYSESEAN GAR2_RAT 376 357 -
MLDSSYSDGEVN GAR1_MOUSE 391 372 -
MLDSSYSDGEVN GAR1_RAT 391 372 -
MLDGNYSDGEVN GAR1_HUMAN 390 371 -
MLDGSYSESEAN GAR2_HUMAN 376 357 -
MLDGTYSEADAN O42157 386 367 -
MLDGTYSEADTN Q9YGQ5 385 366 -
AFDGCYHDGETD GAR3_RAT 379 360 -

Motif 3 width=11
Element Seqn Id St Int Rpt
SELTSSKKKGL GAR2_MOUSE 415 27 -
SELTSSRKKGL GAR2_RAT 415 27 -
SERGSPQRKGQ GAR1_MOUSE 426 23 -
SERGSPQRKSQ GAR1_RAT 426 23 -
SERSSPQRKSQ GAR1_HUMAN 425 23 -
GEANAARKKGL GAR2_HUMAN 415 27 -
NEPTGTKKKGI O42157 427 29 -
ESTTTKKKKSL Q9YGQ5 433 36 -
ADSSQIKRKSL GAR3_RAT 415 24 -