GLRA3_HUMAN
ID GLRA3_HUMAN Reviewed; 464 AA.
AC O75311; D3DP44; O75816; Q5D0E3;
DT 15-DEC-1998, integrated into UniProtKB/Swiss-Prot.
DT 17-OCT-2006, sequence version 2.
DT 03-AUG-2022, entry version 199.
DE RecName: Full=Glycine receptor subunit alpha-3;
DE Flags: Precursor;
GN Name=GLRA3;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORMS ALPHA-3K AND ALPHA-3L),
RP FUNCTION, SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RC TISSUE=Fetal brain;
RX PubMed=9677400; DOI=10.1074/jbc.273.31.19708;
RA Nikolic Z., Laube B., Weber R.G., Lichter P., Kioschis P., Poustka A.,
RA Muelhardt C., Becker C.-M.;
RT "The human glycine receptor subunit alpha3. GLRA3 gene structure,
RT chromosomal localization, and functional characterization of alternative
RT transcripts.";
RL J. Biol. Chem. 273:19708-19714(1998).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM ALPHA-3L).
RC TISSUE=Brain;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [4] {ECO:0007744|PDB:5CFB}
RP X-RAY CRYSTALLOGRAPHY (3.04 ANGSTROMS) OF 34-342 AND 419-460 IN COMPLEX
RP WITH STRYCHNINE, FUNCTION, SUBUNIT, SUBCELLULAR LOCATION, TOPOLOGY,
RP DISULFIDE BONDS, GLYCOSYLATION AT ASN-71, AND DOMAIN.
RX PubMed=26416729; DOI=10.1038/nature14972;
RA Huang X., Chen H., Michelsen K., Schneider S., Shaffer P.L.;
RT "Crystal structure of human glycine receptor-alpha3 bound to antagonist
RT strychnine.";
RL Nature 526:277-280(2015).
CC -!- FUNCTION: Glycine receptors are ligand-gated chloride channels. Channel
CC opening is triggered by extracellular glycine (PubMed:9677400,
CC PubMed:26416729). Channel characteristics depend on the subunit
CC composition; heteropentameric channels display faster channel closure
CC (By similarity). Plays an important role in the down-regulation of
CC neuronal excitability (By similarity). Contributes to the generation of
CC inhibitory postsynaptic currents (By similarity). Contributes to
CC increased pain perception in response to increased prostaglandin E2
CC levels (By similarity). Plays a role in cellular responses to ethanol
CC (By similarity). {ECO:0000250|UniProtKB:P24524,
CC ECO:0000250|UniProtKB:Q91XP5, ECO:0000269|PubMed:26416729,
CC ECO:0000269|PubMed:9677400}.
CC -!- SUBUNIT: Homopentamer (in vitro) (PubMed:26416729). Heteropentamer
CC composed of GLRA3 and GLRB. Both homopentamers and heteropentamers form
CC functional ion channels, but their characteristics are subtly different
CC (By similarity). {ECO:0000250|UniProtKB:P24524,
CC ECO:0000269|PubMed:26416729}.
CC -!- SUBCELLULAR LOCATION: Postsynaptic cell membrane
CC {ECO:0000250|UniProtKB:P24524}; Multi-pass membrane protein
CC {ECO:0000305}. Perikaryon {ECO:0000250|UniProtKB:P24524}. Cell
CC projection, dendrite {ECO:0000250|UniProtKB:P24524}. Synapse
CC {ECO:0000250|UniProtKB:P24524}. Cell membrane
CC {ECO:0000269|PubMed:26416729, ECO:0000269|PubMed:9677400}; Multi-pass
CC membrane protein {ECO:0000269|PubMed:26416729}. Note=Partially
CC colocalizes with GPHN that is known to mediate receptor clustering at
CC postsynaptic membranes. {ECO:0000250|UniProtKB:P24524}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=Alpha-3L;
CC IsoId=O75311-1; Sequence=Displayed;
CC Name=Alpha-3K;
CC IsoId=O75311-2; Sequence=VSP_000084;
CC -!- TISSUE SPECIFICITY: Widely distributed throughout the central nervous
CC system. {ECO:0000269|PubMed:9677400}.
CC -!- DOMAIN: The N-terminal domain carries structural determinants essential
CC for agonist and antagonist binding. The channel pore is formed by
CC pentameric assembly of the second transmembrane domain from all five
CC subunits (PubMed:26416729). The cytoplasmic loop is an important
CC determinant of channel inactivation kinetics.
CC {ECO:0000269|PubMed:26416729, ECO:0000305}.
CC -!- PTM: Phosphorylated by PKA; this causes down-regulation of channel
CC activity. {ECO:0000250|UniProtKB:P24524}.
CC -!- MISCELLANEOUS: The alpha subunit binds strychnine.
CC {ECO:0000269|PubMed:26416729}.
CC -!- SIMILARITY: Belongs to the ligand-gated ion channel (TC 1.A.9) family.
CC Glycine receptor (TC 1.A.9.3) subfamily. GLRA3 sub-subfamily.
CC {ECO:0000305}.
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DR EMBL; AF017724; AAC39919.1; -; Genomic_DNA.
DR EMBL; AF017715; AAC39919.1; JOINED; Genomic_DNA.
DR EMBL; AF017716; AAC39919.1; JOINED; Genomic_DNA.
DR EMBL; AF017717; AAC39919.1; JOINED; Genomic_DNA.
DR EMBL; AF017718; AAC39919.1; JOINED; Genomic_DNA.
DR EMBL; AF017719; AAC39919.1; JOINED; Genomic_DNA.
DR EMBL; AF017720; AAC39919.1; JOINED; Genomic_DNA.
DR EMBL; AF017721; AAC39919.1; JOINED; Genomic_DNA.
DR EMBL; AF017722; AAC39919.1; JOINED; Genomic_DNA.
DR EMBL; AF017723; AAC39919.1; JOINED; Genomic_DNA.
DR EMBL; U93917; AAC39917.1; -; mRNA.
DR EMBL; CH471056; EAX04730.1; -; Genomic_DNA.
DR EMBL; CH471056; EAX04732.1; -; Genomic_DNA.
DR EMBL; BC036086; AAH36086.1; -; mRNA.
DR CCDS; CCDS3822.1; -. [O75311-1]
DR CCDS; CCDS43283.1; -. [O75311-2]
DR RefSeq; NP_001036008.1; NM_001042543.2. [O75311-2]
DR RefSeq; NP_006520.2; NM_006529.3. [O75311-1]
DR PDB; 5CFB; X-ray; 3.04 A; A/B/C/D/E=34-342, A/B/C/D/E=419-460.
DR PDB; 5TIN; X-ray; 2.61 A; A/B/C/D/E=34-342, A/B/C/D/E=419-460.
DR PDB; 5TIO; X-ray; 3.25 A; A/B/C/D/E=34-342, A/B/C/D/E=419-460.
DR PDB; 5VDH; X-ray; 2.85 A; A/B/C/D/E=34-342, A/B/C/D/E=419-460.
DR PDB; 5VDI; X-ray; 3.10 A; A/B/C/D/E=34-342, A/B/C/D/E=419-460.
DR PDBsum; 5CFB; -.
DR PDBsum; 5TIN; -.
DR PDBsum; 5TIO; -.
DR PDBsum; 5VDH; -.
DR PDBsum; 5VDI; -.
DR AlphaFoldDB; O75311; -.
DR SMR; O75311; -.
DR BioGRID; 113705; 9.
DR DIP; DIP-61773N; -.
DR IntAct; O75311; 2.
DR STRING; 9606.ENSP00000274093; -.
DR BindingDB; O75311; -.
DR ChEMBL; CHEMBL1075092; -.
DR DrugBank; DB09061; Cannabidiol.
DR DrugBank; DB00145; Glycine.
DR DrugBank; DB00431; Lindane.
DR DrugBank; DB14009; Medical Cannabis.
DR DrugBank; DB01043; Memantine.
DR DrugBank; DB14011; Nabiximols.
DR DrugBank; DB00466; Picrotoxin.
DR DrugBank; DB01956; Taurine.
DR DrugCentral; O75311; -.
DR GuidetoPHARMACOLOGY; 425; -.
DR TCDB; 1.A.9.3.1; the neurotransmitter receptor, cys loop, ligand-gated ion channel (lic) family.
DR GlyGen; O75311; 1 site.
DR iPTMnet; O75311; -.
DR PhosphoSitePlus; O75311; -.
DR BioMuta; GLRA3; -.
DR MassIVE; O75311; -.
DR PaxDb; O75311; -.
DR PeptideAtlas; O75311; -.
DR PRIDE; O75311; -.
DR ABCD; O75311; 3 sequenced antibodies.
DR Antibodypedia; 28583; 101 antibodies from 23 providers.
DR DNASU; 8001; -.
DR Ensembl; ENST00000274093.8; ENSP00000274093.3; ENSG00000145451.13. [O75311-1]
DR Ensembl; ENST00000340217.5; ENSP00000345284.5; ENSG00000145451.13. [O75311-2]
DR GeneID; 8001; -.
DR KEGG; hsa:8001; -.
DR MANE-Select; ENST00000274093.8; ENSP00000274093.3; NM_006529.4; NP_006520.2.
DR UCSC; uc003ity.3; human. [O75311-1]
DR CTD; 8001; -.
DR DisGeNET; 8001; -.
DR GeneCards; GLRA3; -.
DR HGNC; HGNC:4328; GLRA3.
DR HPA; ENSG00000145451; Group enriched (brain, breast).
DR MIM; 600421; gene.
DR neXtProt; NX_O75311; -.
DR OpenTargets; ENSG00000145451; -.
DR PharmGKB; PA28729; -.
DR VEuPathDB; HostDB:ENSG00000145451; -.
DR eggNOG; KOG3644; Eukaryota.
DR GeneTree; ENSGT00940000158368; -.
DR HOGENOM; CLU_010920_1_4_1; -.
DR InParanoid; O75311; -.
DR OMA; VMPKNPD; -.
DR PhylomeDB; O75311; -.
DR TreeFam; TF315453; -.
DR PathwayCommons; O75311; -.
DR Reactome; R-HSA-112314; Neurotransmitter receptors and postsynaptic signal transmission.
DR SignaLink; O75311; -.
DR SIGNOR; O75311; -.
DR BioGRID-ORCS; 8001; 6 hits in 1069 CRISPR screens.
DR ChiTaRS; GLRA3; human.
DR GeneWiki; GLRA3; -.
DR GenomeRNAi; 8001; -.
DR Pharos; O75311; Tchem.
DR PRO; PR:O75311; -.
DR Proteomes; UP000005640; Chromosome 4.
DR RNAct; O75311; protein.
DR Bgee; ENSG00000145451; Expressed in pancreatic ductal cell and 57 other tissues.
DR Genevisible; O75311; HS.
DR GO; GO:0070161; C:anchoring junction; IEA:UniProtKB-KW.
DR GO; GO:0030425; C:dendrite; IEA:UniProtKB-SubCell.
DR GO; GO:0016935; C:glycine-gated chloride channel complex; IDA:UniProtKB.
DR GO; GO:0005887; C:integral component of plasma membrane; IDA:UniProtKB.
DR GO; GO:0043005; C:neuron projection; IBA:GO_Central.
DR GO; GO:0043204; C:perikaryon; IEA:UniProtKB-SubCell.
DR GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR GO; GO:0045211; C:postsynaptic membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0045202; C:synapse; IBA:GO_Central.
DR GO; GO:0005231; F:excitatory extracellular ligand-gated ion channel activity; IBA:GO_Central.
DR GO; GO:0016934; F:extracellularly glycine-gated chloride channel activity; IDA:UniProtKB.
DR GO; GO:0016594; F:glycine binding; IEA:InterPro.
DR GO; GO:0022852; F:glycine-gated chloride ion channel activity; IDA:UniProtKB.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0030594; F:neurotransmitter receptor activity; IBA:GO_Central.
DR GO; GO:0004888; F:transmembrane signaling receptor activity; IEA:InterPro.
DR GO; GO:1904315; F:transmitter-gated ion channel activity involved in regulation of postsynaptic membrane potential; IBA:GO_Central.
DR GO; GO:0007268; P:chemical synaptic transmission; IBA:GO_Central.
DR GO; GO:1902476; P:chloride transmembrane transport; IDA:UniProtKB.
DR GO; GO:0034220; P:ion transmembrane transport; IBA:GO_Central.
DR GO; GO:0050877; P:nervous system process; IBA:GO_Central.
DR GO; GO:0007218; P:neuropeptide signaling pathway; IBA:GO_Central.
DR GO; GO:0051260; P:protein homooligomerization; IDA:UniProtKB.
DR GO; GO:0042391; P:regulation of membrane potential; IBA:GO_Central.
DR GO; GO:0043200; P:response to amino acid; IBA:GO_Central.
DR GO; GO:0007165; P:signal transduction; IBA:GO_Central.
DR GO; GO:0060012; P:synaptic transmission, glycinergic; IBA:GO_Central.
DR Gene3D; 1.20.58.390; -; 1.
DR Gene3D; 2.70.170.10; -; 1.
DR InterPro; IPR006028; GABAA/Glycine_rcpt.
DR InterPro; IPR008127; Glycine_rcpt_A.
DR InterPro; IPR008130; Glycine_rcpt_A3.
DR InterPro; IPR006202; Neur_chan_lig-bd.
DR InterPro; IPR036734; Neur_chan_lig-bd_sf.
DR InterPro; IPR006201; Neur_channel.
DR InterPro; IPR036719; Neuro-gated_channel_TM_sf.
DR InterPro; IPR038050; Neuro_actylchol_rec.
DR InterPro; IPR006029; Neurotrans-gated_channel_TM.
DR InterPro; IPR018000; Neurotransmitter_ion_chnl_CS.
DR PANTHER; PTHR18945; PTHR18945; 1.
DR Pfam; PF02931; Neur_chan_LBD; 1.
DR Pfam; PF02932; Neur_chan_memb; 1.
DR PRINTS; PR00253; GABAARECEPTR.
DR PRINTS; PR01673; GLYRALPHA.
DR PRINTS; PR01676; GLYRALPHA3.
DR PRINTS; PR00252; NRIONCHANNEL.
DR SUPFAM; SSF63712; SSF63712; 1.
DR SUPFAM; SSF90112; SSF90112; 1.
DR TIGRFAMs; TIGR00860; LIC; 1.
DR PROSITE; PS00236; NEUROTR_ION_CHANNEL; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Cell membrane; Cell projection;
KW Chloride; Chloride channel; Disulfide bond; Glycoprotein; Ion channel;
KW Ion transport; Ligand-gated ion channel; Membrane; Metal-binding;
KW Phosphoprotein; Postsynaptic cell membrane; Receptor; Reference proteome;
KW Signal; Synapse; Transmembrane; Transmembrane helix; Transport; Zinc.
FT SIGNAL 1..33
FT /evidence="ECO:0000255"
FT CHAIN 34..464
FT /note="Glycine receptor subunit alpha-3"
FT /id="PRO_0000000419"
FT TOPO_DOM 34..255
FT /note="Extracellular"
FT /evidence="ECO:0000269|PubMed:26416729"
FT TRANSMEM 256..277
FT /note="Helical; Name=1"
FT /evidence="ECO:0000269|PubMed:26416729"
FT TOPO_DOM 278..282
FT /note="Cytoplasmic"
FT /evidence="ECO:0000269|PubMed:26416729"
FT TRANSMEM 283..303
FT /note="Helical; Name=2"
FT /evidence="ECO:0000269|PubMed:26416729"
FT TOPO_DOM 304..314
FT /note="Extracellular"
FT /evidence="ECO:0000269|PubMed:26416729"
FT TRANSMEM 315..335
FT /note="Helical; Name=3"
FT /evidence="ECO:0000269|PubMed:26416729"
FT TOPO_DOM 336..430
FT /note="Cytoplasmic"
FT /evidence="ECO:0000269|PubMed:26416729"
FT TRANSMEM 431..451
FT /note="Helical; Name=4"
FT /evidence="ECO:0000269|PubMed:26416729"
FT TOPO_DOM 452..464
FT /note="Extracellular"
FT /evidence="ECO:0000269|PubMed:26416729"
FT BINDING 225
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000250|UniProtKB:P23415"
FT BINDING 227
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000250|UniProtKB:P23415"
FT BINDING 235..240
FT /ligand="strychnine"
FT /ligand_id="ChEBI:CHEBI:90700"
FT /evidence="ECO:0000269|PubMed:26416729"
FT BINDING 248
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000250|UniProtKB:P23415"
FT SITE 294
FT /note="Important for obstruction of the ion pore in the
FT closed conformation"
FT /evidence="ECO:0000269|PubMed:26416729"
FT MOD_RES 370
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q91XP5"
FT MOD_RES 379
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q91XP5"
FT CARBOHYD 71
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255, ECO:0000269|PubMed:26416729,
FT ECO:0007744|PDB:5CFB"
FT DISULFID 171..185
FT /evidence="ECO:0000269|PubMed:26416729,
FT ECO:0007744|PDB:5CFB"
FT DISULFID 231..242
FT /evidence="ECO:0000269|PubMed:26416729,
FT ECO:0007744|PDB:5CFB"
FT VAR_SEQ 358..372
FT /note="Missing (in isoform Alpha-3K)"
FT /evidence="ECO:0000303|PubMed:9677400"
FT /id="VSP_000084"
FT CONFLICT 460
FT /note="H -> HH (in Ref. 1; AAC39919)"
FT /evidence="ECO:0000305"
FT HELIX 43..51
FT /evidence="ECO:0007829|PDB:5TIN"
FT TURN 53..55
FT /evidence="ECO:0007829|PDB:5TIN"
FT TURN 63..66
FT /evidence="ECO:0007829|PDB:5TIN"
FT STRAND 70..85
FT /evidence="ECO:0007829|PDB:5TIN"
FT TURN 86..89
FT /evidence="ECO:0007829|PDB:5TIN"
FT STRAND 90..102
FT /evidence="ECO:0007829|PDB:5TIN"
FT HELIX 104..106
FT /evidence="ECO:0007829|PDB:5TIN"
FT STRAND 114..118
FT /evidence="ECO:0007829|PDB:5TIN"
FT HELIX 120..125
FT /evidence="ECO:0007829|PDB:5TIN"
FT STRAND 131..133
FT /evidence="ECO:0007829|PDB:5TIN"
FT STRAND 136..141
FT /evidence="ECO:0007829|PDB:5TIN"
FT STRAND 144..146
FT /evidence="ECO:0007829|PDB:5TIN"
FT STRAND 149..154
FT /evidence="ECO:0007829|PDB:5TIN"
FT STRAND 157..170
FT /evidence="ECO:0007829|PDB:5TIN"
FT TURN 176..179
FT /evidence="ECO:0007829|PDB:5TIN"
FT STRAND 182..193
FT /evidence="ECO:0007829|PDB:5TIN"
FT TURN 196..198
FT /evidence="ECO:0007829|PDB:5TIN"
FT STRAND 199..203
FT /evidence="ECO:0007829|PDB:5TIN"
FT STRAND 208..211
FT /evidence="ECO:0007829|PDB:5TIN"
FT STRAND 218..222
FT /evidence="ECO:0007829|PDB:5TIN"
FT STRAND 227..230
FT /evidence="ECO:0007829|PDB:5TIN"
FT STRAND 233..235
FT /evidence="ECO:0007829|PDB:5TIN"
FT STRAND 238..240
FT /evidence="ECO:0007829|PDB:5TIN"
FT STRAND 242..251
FT /evidence="ECO:0007829|PDB:5TIN"
FT HELIX 254..259
FT /evidence="ECO:0007829|PDB:5TIN"
FT HELIX 261..273
FT /evidence="ECO:0007829|PDB:5TIN"
FT HELIX 274..276
FT /evidence="ECO:0007829|PDB:5TIN"
FT HELIX 282..302
FT /evidence="ECO:0007829|PDB:5TIN"
FT TURN 303..306
FT /evidence="ECO:0007829|PDB:5TIN"
FT HELIX 315..340
FT /evidence="ECO:0007829|PDB:5TIN"
FT HELIX 419..450
FT /evidence="ECO:0007829|PDB:5TIN"
SQ SEQUENCE 464 AA; 53800 MW; 8E17A30B3C6E648D CRC64;
MAHVRHFRTL VSGFYFWEAA LLLSLVATKE TDSARSRSAP MSPSDFLDKL MGRTSGYDAR
IRPNFKGPPV NVTCNIFINS FGSIAETTMD YRVNIFLRQK WNDPRLAYSE YPDDSLDLDP
SMLDSIWKPD LFFANEKGAN FHEVTTDNKL LRIFKNGNVL YSIRLTLTLS CPMDLKNFPM
DVQTCIMQLE SFGYTMNDLI FEWQDEAPVQ VAEGLTLPQF LLKEEKDLRY CTKHYNTGKF
TCIEVRFHLE RQMGYYLIQM YIPSLLIVIL SWVSFWINMD AAPARVALGI TTVLTMTTQS
SGSRASLPKV SYVKAIDIWM AVCLLFVFSA LLEYAAVNFV SRQHKELLRF RRKRKNKTEA
FALEKFYRFS DMDDEVRESR FSFTAYGMGP CLQAKDGMTP KGPNHPVQVM PKSPDEMRKV
FIDRAKKIDT ISRACFPLAF LIFNIFYWVI YKILRHEDIH QQQD
