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PR01675

Identifier
GLYRALPHA2  [View Relations]  [View Alignment]  
Accession
PR01675
No. of Motifs
3
Creation Date
14-MAR-2002
Title
Glycine receptor alpha 2 subunit signature
Database References
PRINTS; PR00252 NRIONCHANNEL; PR01673 GLYRALPHA
MIM; 305990
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].
 
In humans, the GLRA2 gene is located on chromosome Xp22.2-22.1 [2]. In situ
hybridisation studies have shown GLRA2 to be expressed in the hippocampus,
cerebral cortex and thalamus. GLRA2 trancripts predominate in the neonatal
and embyonic CNS, and are replaced postnatally by those of GLRA1 and, to a
lesser extent, GLRA3 [5].
 
GLYRALPHA2 is a 3-element fingerprint that provides a signature for glycine
receptor alpha 2 (GLRA2) subunits. The fingerprint was derived from an
initial alignment of 3 sequences: the motifs were drawn from conserved
regions largely spanning the N-terminal two-thirds of the alignment,
focusing on those sections that characterise GLRA2 subunits but distinguish 
them from the rest of the GLRA subunit family - motif 1 resides within the
N-terminal domain; and motifs 2 and 3 lie within the long cytoplasmic loop
between TM domains 3 and 4 [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
GRA2_HUMAN    GRA2_RAT      Q9DES9        
Sequence Titles
GRA2_HUMAN  Glycine receptor alpha-2 chain precursor - Homo sapiens (Human). 
GRA2_RAT Glycine receptor alpha-2* chain precursor (Neonatal isoform) (Glycine receptor strychnine binding subunit) - Rattus norvegicus (Rat).
Q9DES9 GLYCINE RECEPTOR ALPHAZ2 SUBUNIT - Brachydanio rerio (Zebrafish) (Zebra danio).
Scan History
SPTR40_18f 1  300  NSINGLE    
Initial Motifs
Motif 1  width=21
Element Seqn Id St Int Rpt
RTAFCKDHDSRSGKQPSQTLS GRA2_HUMAN 23 23 -
REAFCKDHDSRSGKHPSQTLS GRA2_RAT 23 23 -
SGFFSISLPLCFLYLWQKPMS Q9DES9 22 22 -

Motif 2 width=12
Element Seqn Id St Int Rpt
KRQNKEEDVTRE GRA2_HUMAN 356 312 -
KRQNKEEDVTRE GRA2_RAT 356 312 -
RRQRIEEDLVRE Q9DES9 355 312 -

Motif 3 width=11
Element Seqn Id St Int Rpt
AVKATPANPLP GRA2_HUMAN 388 20 -
AVKATPANPLP GRA2_RAT 388 20 -
AVEGSSVFAPP Q9DES9 388 21 -
Final Motifs
Motif 1  width=21
Element Seqn Id St Int Rpt
RTAFCKDHDSRSGKQPSQTLS GRA2_HUMAN 23 23 -
REAFCKDHDSRSGKHPSQTLS GRA2_RAT 23 23 -
SGFFSISLPLCFLYLWQKPMS Q9DES9 22 22 -

Motif 2 width=12
Element Seqn Id St Int Rpt
KRQNKEEDVTRE GRA2_HUMAN 356 312 -
KRQNKEEDVTRE GRA2_RAT 356 312 -
RRQRIEEDLVRE Q9DES9 355 312 -

Motif 3 width=11
Element Seqn Id St Int Rpt
AVKATPANPLP GRA2_HUMAN 388 20 -
AVKATPANPLP GRA2_RAT 388 20 -
AVEGSSVFAPP Q9DES9 388 21 -