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PR01676

Identifier
GLYRALPHA3  [View Relations]  [View Alignment]  
Accession
PR01676
No. of Motifs
3
Creation Date
14-MAR-2002
Title
Glycine receptor alpha 3 subunit signature
Database References
PRINTS; PR00252 NRIONCHANNEL; PR01673 GLYRALPHA
MIM; 600421
Literature References
1.LOPEZ-CORCUERA, B., GEERLINGS, A. AND ARAGON, C.
Glycine neurotransmitter transporters: an update.
MOL.MEMBR.BIOL. 18(1) 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(5) 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).
 
6. NIKOLIC, Z., LAUBE, B., WEBER, R.G., LICHTER, P., KIOSCHIS, P.,
POUTSKA, A., MULHARDT, C. AND BECKER, C.M.
The human glycine receptor subunit alpha3. Glra3 gene structure,
chromosomal localization, and functional characterization of
alternative transcripts.
J.BIOL.CHEM. 273(31) 19708-19714 (1998).        

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].
 
Using fluorescence in situ hybridisation, the locus of the human GLRA3 gene
was assigned to chromosomal bands 4q33-q34 [6]. GLRA3 is expressed in the
cerebellum, olfactory bulb and hippocampus. GLRA3 trancripts, together with
GLRA1, predominate in the postnatal CNS, replacing GLRA2, which is more
abundant in embryonic and neonatal neurones [5].
 
GLYRALPHA3 is a 3-element fingerprint that provides a signature for glycine
receptor alpha 3 (GLRA3) subunits. The fingerprint was derived from an
initial alignment of 3 sequences: the motifs were drawn from conserved
regions spanning virtually the full alignment length, focusing on those
sections that characterise GLRA3 subunits but distinguish them from the rest
of the GLRA subunit family - motif 1 resides within the N-terminal domain;
motif 2 lies within the long cytoplasmic loop between TM domains 3 and 4; 
and motif 3 lies at the junction of the long cytoplasmic loop and TM4 [4].
A single iteration on SPTR40_18f was required to reach convergence, no
further sequences being identified beyond the starting set.
Summary Information
3 codes involving  3 elements
0 codes involving 2 elements
Composite Feature Index
3333
2000
123
True Positives
GRA3_HUMAN    GRA3_RAT      Q99JC9        
Sequence Titles
GRA3_HUMAN  Glycine receptor alpha-3 chain precursor - Homo sapiens (Human). 
GRA3_RAT Glycine receptor alpha-3 chain precursor - Rattus norvegicus (Rat).
Q99JC9 GLYCINE RECEPTOR ALPHA 3 PRECURSOR - Rattus norvegicus (Rat).
Scan History
SPTR40_18f 1  300  NSINGLE    
Initial Motifs
Motif 1  width=18
Element Seqn Id St Int Rpt
LLSLVATKETNSARSRSA GRA3_RAT 22 22 -
LLSLVATKETNSARSRSA Q99JC9 38 38 -
LLSLVATKETDSARSRSA GRA3_HUMAN 22 22 -

Motif 2 width=23
Element Seqn Id St Int Rpt
RKNKTEAFALEKFYRFSDTDDEV GRA3_RAT 354 314 -
RKNKTEAFALEKFYRFSDTDDEV Q99JC9 370 314 -
RKNKTEAFALEKFYRFSDMDDEV GRA3_HUMAN 354 314 -

Motif 3 width=14
Element Seqn Id St Int Rpt
VVPKGPNHAVQVMP GRA3_RAT 398 21 -
VVPKGPNHAVQVMP Q99JC9 414 21 -
MTPKGPNHPVQVMP GRA3_HUMAN 398 21 -
Final Motifs
Motif 1  width=18
Element Seqn Id St Int Rpt
LLSLVATKETNSARSRSA GRA3_RAT 22 22 -
LLSLVATKETNSARSRSA Q99JC9 38 38 -
LLSLVATKETDSARSRSA GRA3_HUMAN 22 22 -

Motif 2 width=23
Element Seqn Id St Int Rpt
RKNKTEAFALEKFYRFSDTDDEV GRA3_RAT 354 314 -
RKNKTEAFALEKFYRFSDTDDEV Q99JC9 370 314 -
RKNKTEAFALEKFYRFSDMDDEV GRA3_HUMAN 354 314 -

Motif 3 width=14
Element Seqn Id St Int Rpt
VVPKGPNHAVQVMP GRA3_RAT 398 21 -
VVPKGPNHAVQVMP Q99JC9 414 21 -
MTPKGPNHPVQVMP GRA3_HUMAN 398 21 -