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PR01674

Identifier
GLYRALPHA1  [View Relations]  [View Alignment]  
Accession
PR01674
No. of Motifs
3
Creation Date
14-MAR-2002
Title
Glycine receptor alpha 1 subunit signature
Database References
PRINTS; PR00252 NRIONCHANNEL; PR01673 GLYRALPHA
MIM; 138491
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 alpha 1 gene is located on chromosome 5p32 [2]. In situ
hybridisation studies have shown GLRA1 to be expressed in the spinal cord,
brain stem and colliculi. GLRA1 trancripts, together with GLRA3, predominate
in the postnatal CNS, replacing GLRA2, which is more abundant in embryonic
and neonatal neurones [5].
 
GLYRALPHA1 is a 3-element fingerprint that provides a signature for glycine
receptor alpha 1 (GLRA1) subunits. The fingerprint was derived from an
initial alignment of 7 sequences: the motifs were drawn from conserved
regions largely spanning the N-terminal two-thirds of the alignment,
focusing on those sections that characterise GLRA1 subunits but distinguish
them from the rest of the GLRA subunit family - motifs 1 and 2 lie within 
the N-terminal domain; and motif 3 resides 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
7 codes involving  3 elements
0 codes involving 2 elements
Composite Feature Index
3777
2000
123
True Positives
GRA1_BOVIN    GRA1_HUMAN    GRA1_MOUSE    GRA1_RAT      
O93430 Q9GKE9 Q9GKF0
Sequence Titles
GRA1_BOVIN  Glycine receptor alpha-1 chain precursor (48 kDa) (Strychnine binding subunit) - Bos taurus (Bovine). 
GRA1_HUMAN Glycine receptor alpha-1 chain precursor (48 kDa) (Strychnine binding subunit) - Homo sapiens (Human).
GRA1_MOUSE Glycine receptor alpha-1 chain precursor (48 kDa) (Strychnine binding subunit) - Mus musculus (Mouse).
GRA1_RAT Glycine receptor alpha-1 chain precursor (48 kDa) (Strychnine binding subunit) - Rattus norvegicus (Rat).
O93430 GLYCINE RECEPTOR, ALPHAZ1 SUBUNIT - BRACHYDANIO RERIO (ZEBRAFISH) (ZEBRA DANIO).
Q9GKE9 GLYCINE RECEPTOR ALPHA 1 SUBUNIT ISOFORM A - Bos taurus (Bovine).
Q9GKF0 GLYCINE RECEPTOR ALPHA 1 SUBUNIT ISOFORM B - Bos taurus (Bovine).
Scan History
SPTR40_18f 1  300  NSINGLE    
Initial Motifs
Motif 1  width=13
Element Seqn Id St Int Rpt
LRLYLWETIVFFS GRA1_BOVIN 7 7 -
LRLYLWETIVFFS Q9GKF0 7 7 -
LRLYLWETIVFFS Q9GKE9 7 7 -
LRFYLWETIVFFS GRA1_MOUSE 7 7 -
LRFYLWETIVFFS GRA1_RAT 7 7 -
LRLYLSGAIVFFS GRA1_HUMAN 7 7 -
LGIYLWETIVFFS O93430 4 4 -

Motif 2 width=14
Element Seqn Id St Int Rpt
LAASKEAEAARSAS GRA1_BOVIN 20 0 -
LAASKEAEAARSAS Q9GKF0 20 0 -
LAASKEAEAARSAS Q9GKE9 20 0 -
LAASKEAEAARSAP GRA1_MOUSE 20 0 -
LAASKEADAARSAP GRA1_RAT 20 0 -
LAASKEAEAARSAT GRA1_HUMAN 20 0 -
LAASQQAAARKAAS O93430 17 0 -

Motif 3 width=16
Element Seqn Id St Int Rpt
DGISVKGANNSNTTNP GRA1_BOVIN 386 352 -
DGISVKGANNSNTTNP Q9GKF0 378 344 -
DGISVKGANNSNTTNP Q9GKE9 386 352 -
DGISVKGANNNNTTNP GRA1_MOUSE 386 352 -
DGISVKGANNNNTTNP GRA1_RAT 386 352 -
DGISVKGANNSNTTNP GRA1_HUMAN 378 344 -
DGMAIKGNNNNAPTST O93430 374 343 -
Final Motifs
Motif 1  width=13
Element Seqn Id St Int Rpt
LRLYLWETIVFFS GRA1_BOVIN 7 7 -
LRLYLWETIVFFS Q9GKF0 7 7 -
LRLYLWETIVFFS Q9GKE9 7 7 -
LRFYLWETIVFFS GRA1_MOUSE 7 7 -
LRFYLWETIVFFS GRA1_RAT 7 7 -
LRLYLSGAIVFFS GRA1_HUMAN 7 7 -
LGIYLWETIVFFS O93430 4 4 -

Motif 2 width=14
Element Seqn Id St Int Rpt
LAASKEAEAARSAS GRA1_BOVIN 20 0 -
LAASKEAEAARSAS Q9GKF0 20 0 -
LAASKEAEAARSAS Q9GKE9 20 0 -
LAASKEAEAARSAP GRA1_MOUSE 20 0 -
LAASKEADAARSAP GRA1_RAT 20 0 -
LAASKEAEAARSAT GRA1_HUMAN 20 0 -
LAASQQAAARKAAS O93430 17 0 -

Motif 3 width=16
Element Seqn Id St Int Rpt
DGISVKGANNSNTTNP GRA1_BOVIN 386 352 -
DGISVKGANNSNTTNP Q9GKF0 378 344 -
DGISVKGANNSNTTNP Q9GKE9 386 352 -
DGISVKGANNNNTTNP GRA1_MOUSE 386 352 -
DGISVKGANNNNTTNP GRA1_RAT 386 352 -
DGISVKGANNSNTTNP GRA1_HUMAN 378 344 -
DGMAIKGNNNNAPTST O93430 374 343 -