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1.A.9.3.1
Adult strychnine-sensitive glycine-inhibited chloride (anion selective) heteropentameric channel (GlyR; GLRA1) consisting of α1- and β-subunits (Cascio, 2004; Sivilotti, 2010). Ivermectin potentiates glycine-induced channel activation (Wang and Lynch, 2012). Molecular sites for the positive allosteric modulation of glycine receptors by endocannabinoids have been identified (Yévenes and Zeilhofer, 2011). Different subunits contribute asymmetrically to channel conductances via residues in the extracellular domain (Moroni et al., 2011; Xiong et al., 2012). Dominant and recessive mutations in GLRA1 are the major causes of hyperekplexia or startle disease (Gimenez et al., 2012).  Open channel 3-d structures are known (Mowrey et al. 2013).  Desensitization is regulated by interactions between the second and third transmembrane segments which affect the ion channel lumen near its intracellular end. The GABAAR and GlyR pore blocker, picrotoxin (TC# 8.C.1), prevents desensitization (Gielen et al. 2015).  The x-ray structure of the α1 GlyR transmembrane domain has been reported (Moraga-Cid et al. 2015), and residue S296 in hGlyR-alpha1 is involved in potentiation by Delta(9)-tetrahydrocannabinol (THC) (Wells et al. 2015).  The structure has also been elucidated by cryo EM (Du et al. 2015) and by x-ray crystalography (Huang et al. 2015). The latter presented a 3.0 A X-ray structure of the human glycine receptor-alpha3 homopentamer in complex with the high affinity, high-specificity antagonist, strychnine. The structure allowed exploration of the molecular recognition of antagonists. Comparisons with previous structures revealed a mechanism for antagonist-induced inactivation of Cys-loop receptors, involving an expansion of the orthosteric binding site in the extracellular domain that is coupled to closure of the ion pore in the transmembrane domain. The GlyR beta8-beta9 loop is an essential regulator of conformational rearrangements during ion channel opening and closing (Schaefer et al. 2017). Association of GlyR with the anchoring protein, gephyrin (Q9NQX3), is due to  a hydrophobic interaction formed by Phe 330 of gephyrin and Phe 398 and Ile 400 of the GlyR beta-loop (Kim et al. 2006). Alcohols and volatile anesthetics enhance the function of inhibitory glycine receptors (GlyRs) by binding to a single anaesthetic binding site (Roberts et al. 2006). Aromatic residues in the GlyR M1, M3 and M4 α-helices are essential for receptor function (Tang and Lummis 2018). The neurological disorder, startle disease, is caused by glycinergic dysfunction, mainly due to missense mutations in genes encoding GlyR subunits (GLRA1 and GLRB). Another neurological disease with a phenotype similar to startle disease is a special form of stiff-person syndrome (SPS), which is most probably due to the development of GlyR autoantibodies (Schaefer et al. 2018).

Accession Number:P23415
Protein Name:GRA1 aka GLRA1
Length:457
Molecular Weight:52624.00
Species:Homo sapiens (Human) [9606]
Number of TMSs:4
Location1 / Topology2 / Orientation3: Cell junction1 / Multi-pass membrane protein2
Substrate Cl-

Cross database links:

Genevestigator: P23415
eggNOG: prNOG07509
HEGENOM: HBG506497
RefSeq: NP_000162.2    NP_001139512.1   
Entrez Gene ID: 2741   
Pfam: PF02931    PF02932   
Drugbank: Drugbank Link   
OMIM: 138491  gene
149400  phenotype
KEGG: hsa:2741   

Gene Ontology

GO:0030054 C:cell junction
GO:0034707 C:chloride channel complex
GO:0005887 C:integral to plasma membrane
GO:0043231 C:intracellular membrane-bounded organelle
GO:0045211 C:postsynaptic membrane
GO:0016934 F:extracellular-glycine-gated chloride channe...
GO:0016594 F:glycine binding
GO:0005515 F:protein binding
GO:0004872 F:receptor activity
GO:0030977 F:taurine binding
GO:0006821 P:chloride transport
GO:0006936 P:muscle contraction
GO:0051970 P:negative regulation of transmission of nerv...
GO:0007218 P:neuropeptide signaling pathway
GO:0001964 P:startle response

References (16)

[1] “Alpha subunit variants of the human glycine receptor: primary structures, functional expression and chromosomal localization of the corresponding genes.”  Grenningloh G.et.al.   2155780
[2] “Complete sequencing and characterization of 21,243 full-length human cDNAs.”  Ota T.et.al.   14702039
[3] “The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).”  The MGC Project Teamet.al.   15489334
[4] “Mapping of disulfide bonds within the amino-terminal extracellular domain of the inhibitory glycine receptor.”  Vogel N.et.al.   19861413
[5] “NMR structure and backbone dynamics of the extended second transmembrane domain of the human neuronal glycine receptor alpha1 subunit.”  Yushmanov V.E.et.al.   12667090
[6] “Structure and dynamics of the second and third transmembrane domains of human glycine receptor.”  Ma D.et.al.   15952785
[7] “Mutations in the alpha 1 subunit of the inhibitory glycine receptor cause the dominant neurologic disorder, hyperekplexia.”  Shiang R.et.al.   8298642
[8] “Decreased agonist affinity and chloride conductance of mutant glycine receptors associated with human hereditary hyperekplexia.”  Langosch D.et.al.   7925268
[9] “An additional family with Startle disease and a G1192A mutation at the alpha 1 subunit of the inhibitory glycine receptor gene.”  Schorderet D.F.et.al.   7981700
[10] “Evidence for recessive as well as dominant forms of startle disease (hyperekplexia) caused by mutations in the alpha 1 subunit of the inhibitory glycine receptor.”  Rees M.I.et.al.   7881416
[11] “Mutational analysis of familial and sporadic hyperekplexia.”  Shiang R.et.al.   7611730
[12] “A novel mutation (Gln266-->His) in the alpha 1 subunit of the inhibitory glycine-receptor gene (GLRA1) in hereditary hyperekplexia.”  Milani N.et.al.   8571969
[13] “Analysis of GLRA1 in hereditary and sporadic hyperekplexia: a novel mutation in a family cosegregating for hyperekplexia and spastic paraparesis.”  Elmslie F.V.et.al.   8733061
[14] “Startle disease in an Italian family by mutation (K276E): the alpha-subunit of the inhibiting glycine receptor.”  Seri M.et.al.   9067762
[15] “Hyperekplexia phenotype due to compound heterozygosity for GLRA1 gene mutations.”  Vergouwe M.N.et.al.   10514101
[16] “Novel GLRA1 missense mutation (P250T) in dominant hyperekplexia defines an intracellular determinant of glycine receptor channel gating.”  Saul B.et.al.   9920650
Structure:
1MOT   1VRY   2M6B   2M6I   4X5T     

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FASTA formatted sequence
1:	MYSFNTLRLY LWETIVFFSL AASKEAEAAR SAPKPMSPSD FLDKLMGRTS GYDARIRPNF 
61:	KGPPVNVSCN IFINSFGSIA ETTMDYRVNI FLRQQWNDPR LAYNEYPDDS LDLDPSMLDS 
121:	IWKPDLFFAN EKGAHFHEIT TDNKLLRISR NGNVLYSIRI TLTLACPMDL KNFPMDVQTC 
181:	IMQLESFGYT MNDLIFEWQE QGAVQVADGL TLPQFILKEE KDLRYCTKHY NTGKFTCIEA 
241:	RFHLERQMGY YLIQMYIPSL LIVILSWISF WINMDAAPAR VGLGITTVLT MTTQSSGSRA 
301:	SLPKVSYVKA IDIWMAVCLL FVFSALLEYA AVNFVSRQHK ELLRFRRKRR HHKSPMLNLF 
361:	QEDEAGEGRF NFSAYGMGPA CLQAKDGISV KGANNSNTTN PPPAPSKSPE EMRKLFIQRA 
421:	KKIDKISRIG FPMAFLIFNM FYWIIYKIVR REDVHNQ