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PR01677

Identifier
GLYRBETA  [View Relations]  [View Alignment]  
Accession
PR01677
No. of Motifs
4
Creation Date
14-MAR-2002
Title
Glycine receptor beta subunit signature
Database References
PRINTS; PR00252 NRIONCHANNEL
MIM; 138492
Literature References
1.LOPEZ-CORCUERA, B., GEERLINGS, A. AND ARAGON, C.
Glycine neurotransmitter transporters: an update.
MOL.MEMBR.BIOL. 18 13-20 (2001).
 
2. ASHCROFT, F.M.
Glycine receptors.
IN ION CHANNELS AND DISEASE, ACADEMIC PRESS, 2000, PP.313-324.
 
3. LEGENDRE, P.
The glycinergic inhibitory synapse.
CELL.MOL.LIFE SCI. 58 760-793 (2001).
 
4. LEITE, J.F. AND CASCIO, M.
Structure of ligand-gated ion channels: critical assessment of biochemical
data supports novel topology.
MOL.CELL.NEUROSCI. 17 777-792 (2001).
 
5. BETZ, H., KUHSE, J., SCHMIEDEN, J., LAUBE, B., KIRSCH, J. AND HARVEY, R.J.
Structure and functions of inhibitory and excitatory glycine receptors.
ANN.N.Y.ACAD.SCI. 868 667-676 (1999).    

Documentation
Glycine is a majory inhibitory neurotransmitter (NT) in the adult vertebrate
central nervous system (CNS). Glycinergic synapses have a well-established
role in the processing of motor and sensory information that controls
movement, vision and audition [1]. This action of glycine is mediated
through its interaction with the glycine receptor (GlyR): an intrinsic
chloride channel is opened in reponse to agonist binding. The subsequent
influx of anions prevents membrane depolarisation and neuronal firing
induced by exitatory NTs. Strychnine acts as a competitive antagonist of
glycine binding, thereby reducing the activity of inhibitory neurones.
Poisoning with strychnine is characterised by over-excitation, muscle spasms
and convulsions. Whilst glycine is the principal physiological agonsist at
GlyRs, taurine and beta-alanine also behave as agonists [2]. Compounds that
modulate GlyR activity include zinc, some alcohols and anaesthetics,
picrotoxin, cocaine and some anticonvulsants. GlyRs were thought for some
time to be localised exclusively in the brain stem and spinal cord, but have
since been found to be expressed more widely, including the cochlear nuclei,
cerebellar cortex and forebrain [3].
 
GlyRs belong to the ligand-gated ion channel family, which also includes the
inhibitory gamma-aminobutyric acid type A (GABAA) and excitatory nicotinic
acetylcholine (nACh) and serotonin type 3 (5-HT3) receptors [4].
Affinity-purified GlyR was found to contain two glycosylated membrane
proteins of 48kDa and 56kDa, corresponding to alpha and beta subunits,
respectively. Four genes encoding alpha subunits have been identified (GLRA1
to 4), together with a single beta polypeptide (GLRB). The heterogeneity of
alpha subunits is further increased by alternative exon splicing, yielding
two isoforms of GLRA1 to 3 [3]. The characteristics of different GlyR
subtypes, therefore, can be largely explained by their GLRA content.
 
GlyRs are generally believed to adopt a pentameric structure in vivo: five
subunits assemble to form a ring structure with a central pore. Typically, a
stoichiometry of 3:2 (alpha:beta) is observed [2]. GlyR subunits share a
high overall level of sequence similarity both with themselves and with the
subunits of the GABAA and nACh receptors. Four highly conserved segments
have been proposed to correspond to transmembrane (TM) alpha helices (TM1-4), 
the second of which is thought to contribute to the pore wall [3]. A long 
extracellular N-terminal segment preceeds TM1 and a long cytoplasmic loop 
links TM3 and 4. Short cytoplasmic and extracellular loops join TM1-2 and
TM2-3, respectively, and a short C-terminal sequence follows TM4. Studies
using radiolabelled strychnine have shown the alpha subunit to be
responsible for ligand binding, the critical residues for this interaction 
lying within the N-terminal domain [3]. The beta subunit plays a structural
role, contributing one of its TM domains to the pore wall as well as playing
a putative role in postsynaptic clustering of the receptor [5].
 
In several mammalian species, defects in glycinergic transmission are
associated with complex motor disorders. Mutations in the gene encoding
GLRA1 give rise to hyperplexia, or startle disease [5]. This is
characterised by muscular spasms in response to unexpected light or noise
stimuli, similar to the symptoms of sublethal doses of strychnine. The
mutations result in amino acid substitutions within the TM1-2 and TM3-4
loops, suggesting that these regions are involved in the transduction of
ligand binding into channel activation [2].
 
By contrast with GLRA proteins, GLRB is expressed ubiquitously throughout
the CNS, including areas where there is no evidence for GlyRs. The reason
for such widepread expression is unclear, since GLRB is not believed to
assemble with alpha subunits other than those of GlyRs [3]. The GLRB subunit
locus has been mapped to human chromosome 4q32. GlyRs are densely clustered
within spinal cord neurons; this arrangement is thought to be mediated by
gephyrin, a peripheral membrane protein of 93kDa that binds to both GLRB,
via an 18-residue motif on the large cytoplasmic loop, and polymerised
tubulin. It has been proposed that gephyrin acts as a GlyR-cytoskeleton
linker protein [5].
 
GLYRBETA is a 4-element fingerprint that provides a signature for glycine
receptor beta (GLRB) subunits. The fingerprint was derived from an initial
alignment of 4 sequences: the motifs were drawn from conserved regions 
spanning virtually the full alignment length, focusing on those sections
that characterise GLRB subunits but distinguish them from the rest of the
GlyR subunit family - motifs 1 and 2 lie within the N-terminal domain; and
motifs 3 and 4 reside within the long cytoplasmic loop between TM domains 3
and 4. 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  4 elements
0 codes involving 3 elements
0 codes involving 2 elements
Composite Feature Index
44444
30000
20000
1234
True Positives
GRB_HUMAN     GRB_MOUSE     GRB_RAT       Q9GJS9        
Sequence Titles
GRB_HUMAN   Glycine receptor beta chain precursor - Homo sapiens (Human). 
GRB_MOUSE Glycine receptor beta chain precursor - Mus musculus (Mouse).
GRB_RAT Glycine receptor beta chain precursor (58 kDa) - Rattus norvegicus (Rat).
Q9GJS9 GLYCINE RECEPTOR BETA SUBUNIT - Bos taurus (Bovine).
Scan History
SPTR40_18f 1  300  NSINGLE    
Initial Motifs
Motif 1  width=30
Element Seqn Id St Int Rpt
LCPSQQSAEDLARVPANSTSNILNRLLVSY GRB_HUMAN 38 38 -
LCPSQQSAEDLARVPANSTSNILNRLLVSY Q9GJS9 38 38 -
LCPSQQSAEDLARVPPNSTSNILNRLLVSY GRB_RAT 38 38 -
LCPSQQSPEDLARVPPNSTSNILNRLLVSY GRB_MOUSE 38 38 -

Motif 2 width=15
Element Seqn Id St Int Rpt
LKLPSDFRGSDALTV GRB_HUMAN 116 48 -
LKLPSDFRGSDALTV Q9GJS9 116 48 -
LKLPSDFRGSDALTV GRB_RAT 116 48 -
LKLPSDFRGSDALTV GRB_MOUSE 116 48 -

Motif 3 width=23
Element Seqn Id St Int Rpt
GETRCKKVCTSKSDLRSNDFSIV GRB_HUMAN 401 270 -
GETRCKKVCTSKSDLRSNDFSIV Q9GJS9 401 270 -
GETRCKKVCTSKSDLRSNDFSIV GRB_RAT 401 270 -
GETRCKKVCTSKSDLRSNDFSIV GRB_MOUSE 401 270 -

Motif 4 width=19
Element Seqn Id St Int Rpt
RDFELSNYDCYGKPIEVNN GRB_HUMAN 428 4 -
RDFELSNYDCYGKPIEVNN Q9GJS9 428 4 -
RDFELSNYDCYGKPIEVNN GRB_RAT 428 4 -
RDFELSNYDCYGKPIEVNN GRB_MOUSE 428 4 -
Final Motifs
Motif 1  width=30
Element Seqn Id St Int Rpt
LCPSQQSAEDLARVPANSTSNILNRLLVSY GRB_HUMAN 38 38 -
LCPSQQSAEDLARVPANSTSNILNRLLVSY Q9GJS9 38 38 -
LCPSQQSAEDLARVPPNSTSNILNRLLVSY GRB_RAT 38 38 -
LCPSQQSPEDLARVPPNSTSNILNRLLVSY GRB_MOUSE 38 38 -

Motif 2 width=15
Element Seqn Id St Int Rpt
LKLPSDFRGSDALTV GRB_HUMAN 116 48 -
LKLPSDFRGSDALTV Q9GJS9 116 48 -
LKLPSDFRGSDALTV GRB_RAT 116 48 -
LKLPSDFRGSDALTV GRB_MOUSE 116 48 -

Motif 3 width=23
Element Seqn Id St Int Rpt
GETRCKKVCTSKSDLRSNDFSIV GRB_HUMAN 401 270 -
GETRCKKVCTSKSDLRSNDFSIV Q9GJS9 401 270 -
GETRCKKVCTSKSDLRSNDFSIV GRB_RAT 401 270 -
GETRCKKVCTSKSDLRSNDFSIV GRB_MOUSE 401 270 -

Motif 4 width=19
Element Seqn Id St Int Rpt
RDFELSNYDCYGKPIEVNN GRB_HUMAN 428 4 -
RDFELSNYDCYGKPIEVNN Q9GJS9 428 4 -
RDFELSNYDCYGKPIEVNN GRB_RAT 428 4 -
RDFELSNYDCYGKPIEVNN GRB_MOUSE 428 4 -