SPRINT Home UMBER Home Contents Standard Search Advanced Search Relation Search

==SPRINT==> PRINTS View



  selected as


PR01673

Identifier
GLYRALPHA  [View Relations]  [View Alignment]  
Accession
PR01673
No. of Motifs
3
Creation Date
14-MAR-2002
Title
Glycine receptor alpha subunit signature
Database References
PRINTS; PR00252 NRIONCHANNEL; PR01674 GLYRALPHA1; PR01675 GLYRALPHA2
PRINTS; PR01676 GLYRALPHA3
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].
 
GLYRALPHA is a 3-element fingerprint that provides a signature for glycine
receptor alpha (GLRA) subunits. The fingerprint was derived from an initial
alignment of 9 sequences: the motifs were drawn from conserved regions 
largely spanning the N-terminal two-thirds of the alignment, focusing on
those sections that characterise GLRA subunits but distinguish them from 
GLRB polypeptides and other members of the ligand-gated ion channel family -
motifs 1 and 2 lie within the N-terminal domain; and motif 3 resides within
the cytoplasmic loop between TM domains 3 and 4 [4]. Two iterations on 
SPTR40_18f were required to reach convergence, at which point a true set
comprising 13 proteins was identifed.
Summary Information
13 codes involving  3 elements
0 codes involving 2 elements
Composite Feature Index
3131313
2000
123
True Positives
GRA1_BOVIN    GRA1_HUMAN    GRA1_MOUSE    GRA1_RAT      
GRA2_HUMAN GRA2_RAT GRA3_HUMAN GRA3_RAT
O93430 Q99JC9 Q9DES9 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).
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).
GRA3_HUMAN Glycine receptor alpha-3 chain precursor - Homo sapiens (Human).
GRA3_RAT Glycine receptor alpha-3 chain precursor - Rattus norvegicus (Rat).
O93430 GLYCINE RECEPTOR, ALPHAZ1 SUBUNIT - BRACHYDANIO RERIO (ZEBRAFISH) (ZEBRA DANIO).
Q99JC9 GLYCINE RECEPTOR ALPHA 3 PRECURSOR - Rattus norvegicus (Rat).
Q9DES9 GLYCINE RECEPTOR ALPHAZ2 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 2  300  NSINGLE    
Initial Motifs
Motif 1  width=14
Element Seqn Id St Int Rpt
PMSPSDFLDKLMGR GRA3_HUMAN 40 40 -
PMSPSDFLDKLMGR GRA3_RAT 40 40 -
PMSPSDFLDKLMGR GRA1_BOVIN 35 35 -
PMSPSDFLDKLMGR GRA1_HUMAN 35 35 -
PMSPSDFLDKLMGR GRA1_MOUSE 35 35 -
PMSPSDFLDKLMGR GRA1_RAT 35 35 -
TLSPSDFLDKLMGR GRA2_HUMAN 41 41 -
TLSPSDFLDKLMGR GRA2_RAT 41 41 -
PMPPSEFLDKLMGK O93430 31 31 -

Motif 2 width=19
Element Seqn Id St Int Rpt
AYSEYPDDSLDLDPSMLDS GRA3_HUMAN 107 53 -
AYSEYPDDSLDLDPSMLDS GRA3_RAT 107 53 -
AYNEYPDDSLDLDPSMLDS GRA1_BOVIN 102 53 -
AYNEYPDDSLDLDPSMLDS GRA1_HUMAN 102 53 -
AYNEYPDDSLDLDPSMLDS GRA1_MOUSE 102 53 -
AYNEYPDDSLDLDPSMLDS GRA1_RAT 102 53 -
AYSEYPDDSLDLDPSMLDS GRA2_HUMAN 108 53 -
AYSEYPDDSLDLDPSMLDS GRA2_RAT 108 53 -
AYSEYPDDSLDLDPSMLDS O93430 98 53 -

Motif 3 width=14
Element Seqn Id St Int Rpt
AAVNFVSRQHKELL GRA3_HUMAN 335 209 -
AAVNFVSRQHKELL GRA3_RAT 335 209 -
AAVNFVSRQHKELL GRA1_BOVIN 330 209 -
AAVNFVSRQHKELL GRA1_HUMAN 330 209 -
AAVNFVSRQHKELL GRA1_MOUSE 330 209 -
AAVNFVSRQHKELL GRA1_RAT 330 209 -
AAVNFVSRQHKEFL GRA2_HUMAN 336 209 -
AAVNFVSRQHKEFL GRA2_RAT 336 209 -
AAVNFIARQHKELL O93430 326 209 -
Final Motifs
Motif 1  width=14
Element Seqn Id St Int Rpt
PMSPSDFLDKLMGR GRA3_HUMAN 40 40 -
PMSPSDFLDKLMGR Q99JC9 56 56 -
PMSPSDFLDKLMGR GRA3_RAT 40 40 -
PMSPSDFLDKLMGR GRA1_BOVIN 35 35 -
PMSPSDFLDKLMGR GRA1_HUMAN 35 35 -
PMSPSDFLDKLMGR GRA1_MOUSE 35 35 -
PMSPSDFLDKLMGR GRA1_RAT 35 35 -
PMSPSDFLDKLMGR Q9GKE9 35 35 -
PMSPSDFLDKLMGR Q9GKF0 35 35 -
TLSPSDFLDKLMGR GRA2_HUMAN 41 41 -
TLSPSDFLDKLMGR GRA2_RAT 41 41 -
PMSPSDFLDKLMGR Q9DES9 40 40 -
PMPPSEFLDKLMGK O93430 31 31 -

Motif 2 width=19
Element Seqn Id St Int Rpt
AYSEYPDDSLDLDPSMLDS GRA3_HUMAN 107 53 -
AYSEYPDDSLDLDPSMLDS Q99JC9 123 53 -
AYSEYPDDSLDLDPSMLDS GRA3_RAT 107 53 -
AYNEYPDDSLDLDPSMLDS GRA1_BOVIN 102 53 -
AYNEYPDDSLDLDPSMLDS GRA1_HUMAN 102 53 -
AYNEYPDDSLDLDPSMLDS GRA1_MOUSE 102 53 -
AYNEYPDDSLDLDPSMLDS GRA1_RAT 102 53 -
AYNEYPDDSLDLDPSMLDS Q9GKE9 102 53 -
AYNEYPDDSLDLDPSMLDS Q9GKF0 102 53 -
AYSEYPDDSLDLDPSMLDS GRA2_HUMAN 108 53 -
AYSEYPDDSLDLDPSMLDS GRA2_RAT 108 53 -
AYSEYPDASLDLDPSMLDS Q9DES9 107 53 -
AYSEYPDDSLDLDPSMLDS O93430 98 53 -

Motif 3 width=14
Element Seqn Id St Int Rpt
AAVNFVSRQHKELL GRA3_HUMAN 335 209 -
AAVNFVSRQHKELL Q99JC9 351 209 -
AAVNFVSRQHKELL GRA3_RAT 335 209 -
AAVNFVSRQHKELL GRA1_BOVIN 330 209 -
AAVNFVSRQHKELL GRA1_HUMAN 330 209 -
AAVNFVSRQHKELL GRA1_MOUSE 330 209 -
AAVNFVSRQHKELL GRA1_RAT 330 209 -
AAVNFVSRQHKELL Q9GKE9 330 209 -
AAVNFVSRQHKELL Q9GKF0 330 209 -
AAVNFVSRQHKEFL GRA2_HUMAN 336 209 -
AAVNFVSRQHKEFL GRA2_RAT 336 209 -
AAVNFVSRQHKEFI Q9DES9 335 209 -
AAVNFIARQHKELL O93430 326 209 -