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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:O75311
Protein Name:Glycine receptor subunit alpha-3 aka GLRA3
Length:464
Molecular Weight:53800.00
Species:Homo sapiens (Human) [9606]
Number of TMSs:4
Location1 / Topology2 / Orientation3: Cell junction1 / Multi-pass membrane protein2
Substrate Cl-

Cross database links:

Genevestigator: O75311
eggNOG: prNOG06347
HEGENOM: HBG506497
RefSeq: NP_001036008.1    NP_006520.2   
Entrez Gene ID: 8001   
Pfam: PF02931    PF02932   
Drugbank: Drugbank Link   
OMIM: 600421  gene
KEGG: hsa:8001   

Gene Ontology

GO:0030054 C:cell junction
GO:0034707 C:chloride channel complex
GO:0045211 C:postsynaptic membrane
GO:0016934 F:extracellular-glycine-gated chloride channe...
GO:0004872 F:receptor activity
GO:0006821 P:chloride transport
GO:0007268 P:synaptic transmission

References (3)

[1] “The human glycine receptor subunit alpha3. GLRA3 gene structure, chromosomal localization, and functional characterization of alternative transcripts.”  Nikolic Z.et.al.   9677400
[2] “The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).”  The MGC Project Teamet.al.   15489334
[3] “Automated phosphoproteome analysis for cultured cancer cells by two-dimensional nanoLC-MS using a calcined titania/C18 biphasic column.”  Imami K.et.al.   18187866
Structure:
5CFB     

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FASTA formatted sequence
1:	MAHVRHFRTL VSGFYFWEAA LLLSLVATKE TDSARSRSAP MSPSDFLDKL MGRTSGYDAR 
61:	IRPNFKGPPV NVTCNIFINS FGSIAETTMD YRVNIFLRQK WNDPRLAYSE YPDDSLDLDP 
121:	SMLDSIWKPD LFFANEKGAN FHEVTTDNKL LRIFKNGNVL YSIRLTLTLS CPMDLKNFPM 
181:	DVQTCIMQLE SFGYTMNDLI FEWQDEAPVQ VAEGLTLPQF LLKEEKDLRY CTKHYNTGKF 
241:	TCIEVRFHLE RQMGYYLIQM YIPSLLIVIL SWVSFWINMD AAPARVALGI TTVLTMTTQS 
301:	SGSRASLPKV SYVKAIDIWM AVCLLFVFSA LLEYAAVNFV SRQHKELLRF RRKRKNKTEA 
361:	FALEKFYRFS DMDDEVRESR FSFTAYGMGP CLQAKDGMTP KGPNHPVQVM PKSPDEMRKV 
421:	FIDRAKKIDT ISRACFPLAF LIFNIFYWVI YKILRHEDIH QQQD