ID TRFR_HUMAN Reviewed; 398 AA. AC P34981; Q2M339; DT 01-FEB-1994, integrated into UniProtKB/Swiss-Prot. DT 01-FEB-1994, sequence version 1. DT 02-SEP-2026, entry version 201. DE RecName: Full=Thyrotropin-releasing hormone receptor; DE Short=TRH-R; DE AltName: Full=Thyroliberin receptor; GN Name=TRHR; 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 [MRNA]. RX PubMed=8395824; DOI=10.1006/bbrc.1993.2027; RA Matre V., Karlsen H.E., Wright M.S., Lundell I., Fjeldheim K., RA Gabrielsen O.S., Larhammar D., Gautvik K.M.; RT "Molecular cloning of a functional human thyrotropin-releasing hormone RT receptor."; RL Biochem. Biophys. Res. Commun. 195:179-185(1993). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA]. RC TISSUE=Pituitary; RX PubMed=8396925; DOI=10.1006/bbrc.1993.2107; RA Yamada M., Monden T., Satoh T., Satoh N., Murakami M., Iriuchijima T., RA Kakegawa T., Mori M.; RT "Pituitary adenomas of patients with acromegaly express thyrotropin- RT releasing hormone receptor messenger RNA: cloning and functional expression RT of the human thyrotropin-releasing hormone receptor gene."; RL Biochem. Biophys. Res. Commun. 195:737-745(1993). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA]. RX PubMed=8243797; DOI=10.1016/0303-7207(93)90043-j; RA Duthie S.M., Taylor P.L., Anderson L., Cook J., Eidne K.A.; RT "Cloning and functional characterisation of the human TRH receptor."; RL Mol. Cell. Endocrinol. 95:R11-R15(1993). RN [4] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RX PubMed=7918619; DOI=10.1016/0167-4781(94)90046-9; RA Hinuma S., Hosoya M., Ogi K., Tanaka H., Nagai Y., Onda H.; RT "Molecular cloning and functional expression of a human thyrotropin- RT releasing hormone (TRH) receptor gene."; RL Biochim. Biophys. Acta 1219:251-259(1994). RN [5] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RX PubMed=8703031; DOI=10.1074/jbc.271.36.22183; RA Iwasaki T., Yamada M., Satoh T., Konaka S., Ren Y., Hashimoto K., Kohga H., RA Kato Y., Mori M.; RT "Genomic organization and promoter function of the human thyrotropin- RT releasing hormone receptor gene."; RL J. Biol. Chem. 271:22183-22188(1996). RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Pituitary; RA Kopatz S.A., Aronstam R.S., Sharma S.V.; RT "cDNA clones of human proteins involved in signal transduction sequenced by RT the Guthrie cDNA resource center (www.cdna.org)."; RL Submitted (DEC-2003) to the EMBL/GenBank/DDBJ databases. RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. 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 [8] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-263. RC TISSUE=Placenta; RX PubMed=9886052; DOI=10.1046/j.1471-4159.1999.0720040.x; RA Matre V., Hovring P.I., Orstavik S., Frengen E., Rian E., Velickovic Z., RA Murray-Mcintosh R.P., Gautvik K.M.; RT "Structural and functional organization of the gene encoding the human RT thyrotropin-releasing hormone receptor."; RL J. Neurochem. 72:40-50(1999). RN [9] RP DISULFIDE BOND. RX PubMed=8770906; DOI=10.1210/endo.137.7.8770906; RA Cook J.V., McGregor A., Lee T., Milligan G., Eidne K.A.; RT "A disulfide bonding interaction role for cysteines in the extracellular RT domain of the thyrotropin-releasing hormone receptor."; RL Endocrinology 137:2851-2858(1996). RN [10] RP FUNCTION, INVOLVEMENT IN CHNG7, VARIANTS CHNG7 17-ARG--SER-398 DEL AND RP 115-SER--ALA-118 DELINS THR, AND CHARACTERIZATION OF VARIANTS CHNG7 RP 17-ARG--SER-398 DEL AND 115-SER--ALA-118 DELINS THR. RX PubMed=9141550; DOI=10.1210/jcem.82.5.3918; RA Collu R., Tang J., Castagne J., Lagace G., Masson N., Huot C., Deal C., RA Delvin E., Faccenda E., Eidne K.A., Van Vliet G.; RT "A novel mechanism for isolated central hypothyroidism: inactivating RT mutations in the thyrotropin-releasing hormone receptor gene."; RL J. Clin. Endocrinol. Metab. 82:1561-1565(1997). RN [11] RP INVOLVEMENT IN CHNG7, AND VARIANT CHNG7 17-ARG--SER-398 DEL. RX PubMed=19213692; DOI=10.1056/nejmc0808557; RA Bonomi M., Busnelli M., Beck-Peccoz P., Costanzo D., Antonica F., Dolci C., RA Pilotta A., Buzi F., Persani L.; RT "A family with complete resistance to thyrotropin-releasing hormone."; RL N. Engl. J. Med. 360:731-734(2009). RN [12] RP FUNCTION, SUBCELLULAR LOCATION, INVOLVEMENT IN CHNG7, VARIANT CHNG7 ARG-81, RP AND CHARACTERIZATION OF VARIANT CHNG7 ARG-81. RX PubMed=26735259; DOI=10.1210/jc.2015-3916; RA Koulouri O., Nicholas A.K., Schoenmakers E., Mokrosinski J., Lane F., RA Cole T., Kirk J., Farooqi I.S., Chatterjee V.K., Gurnell M., RA Schoenmakers N.; RT "A novel thyrotropin-releasing hormone receptor missense mutation (P81R) in RT central congenital hypothyroidism."; RL J. Clin. Endocrinol. Metab. 101:847-851(2016). RN [13] RP FUNCTION, INVOLVEMENT IN CHNG7, VARIANT CHNG7 THR-131, AND CHARACTERIZATION RP OF VARIANT CHNG7 THR-131. RX PubMed=28419241; DOI=10.1210/jc.2016-3977; RA Garcia M., Gonzalez de Buitrago J., Jimenez-Roses M., Pardo L., RA Hinkle P.M., Moreno J.C.; RT "Central hypothyroidism due to a TRHR mutation causing impaired ligand RT affinity and transactivation of Gq."; RL J. Clin. Endocrinol. Metab. 102:2433-2442(2017). CC -!- FUNCTION: Receptor for thyrotropin-releasing hormone (TRH). Upon ligand CC binding, this G protein-coupled receptor triggers activation of the CC phosphatidylinositol (IP3)-calcium-protein kinase C (PKC) pathway. CC {ECO:0000269|PubMed:26735259, ECO:0000269|PubMed:9141550}. CC -!- INTERACTION: CC P34981; P11117: ACP2; NbExp=2; IntAct=EBI-18055230, EBI-2907070; CC P34981; Q86Z23: C1QL4; NbExp=3; IntAct=EBI-18055230, EBI-12062109; CC P34981; P21964: COMT; NbExp=3; IntAct=EBI-18055230, EBI-372265; CC P34981; P52803: EFNA5; NbExp=3; IntAct=EBI-18055230, EBI-1753674; CC P34981; Q96D05-2: FAM241B; NbExp=3; IntAct=EBI-18055230, EBI-12118888; CC P34981; P29033: GJB2; NbExp=3; IntAct=EBI-18055230, EBI-3905204; CC P34981; Q9Y5U9: IER3IP1; NbExp=3; IntAct=EBI-18055230, EBI-725665; CC P34981; Q0D2K0: NIPAL4; NbExp=3; IntAct=EBI-18055230, EBI-9550165; CC P34981; I3L0A0: PEDS1-UBE2V1; NbExp=3; IntAct=EBI-18055230, EBI-12213001; CC P34981; Q9NP94: SLC39A2; NbExp=3; IntAct=EBI-18055230, EBI-12898013; CC P34981; Q9NUM3: SLC39A9; NbExp=3; IntAct=EBI-18055230, EBI-2823239; CC P34981; Q8IVJ1: SLC41A1; NbExp=3; IntAct=EBI-18055230, EBI-12266234; CC P34981; Q9UIK5: TMEFF2; NbExp=3; IntAct=EBI-18055230, EBI-11423693; CC P34981; A2RU14: TMEM218; NbExp=3; IntAct=EBI-18055230, EBI-10173151; CC P34981; Q8WW34-2: TMEM239; NbExp=3; IntAct=EBI-18055230, EBI-11528917; CC P34981; Q9Y385: UBE2J1; NbExp=3; IntAct=EBI-18055230, EBI-988826; CC P34981; Q96EC8: YIPF6; NbExp=3; IntAct=EBI-18055230, EBI-751210; CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:26735259}; CC Multi-pass membrane protein {ECO:0000255}. CC -!- DISEASE: Hypothyroidism, congenital, non-goitrous, 7 (CHNG7) CC [MIM:618573]: A form of central hypothyroidism, a disorder CC characterized by sub-optimal thyroid hormone secretion, due to CC insufficient stimulation by thyrotropin of an otherwise normal thyroid CC gland. It may be caused by congenital or acquired disorders of the CC pituitary gland or hypothalamus. CHNG7 is a congenital, autosomal CC recessive form characterized by normal-to-low T4 and normal-to-high CC thyrotropin levels, and reduced or absent pituitary responsiveness to CC thyrotropin-releasing hormone. Patients may exhibit short stature, CC growth retardation, and delayed bone age, as well as lethargy or CC fatigue. {ECO:0000269|PubMed:19213692, ECO:0000269|PubMed:26735259, CC ECO:0000269|PubMed:28419241, ECO:0000269|PubMed:9141550}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- SIMILARITY: Belongs to the G protein-coupled receptor 1 family. CC {ECO:0000255|PROSITE-ProRule:PRU00521}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; D16845; BAA04120.1; -; mRNA. DR EMBL; X75071; CAA52965.1; -; mRNA. DR EMBL; X72089; CAA50979.1; -; mRNA. DR EMBL; S75283; AAB32222.1; -; Genomic_DNA. DR EMBL; S75281; AAB32222.1; JOINED; Genomic_DNA. DR EMBL; D85376; BAA12796.1; -; Genomic_DNA. DR EMBL; AY493373; AAR84356.1; -; mRNA. DR EMBL; BC105045; AAI05046.1; -; mRNA. DR EMBL; BC113360; AAI13361.1; -; mRNA. DR EMBL; AJ011701; CAA09746.1; -; Genomic_DNA. DR CCDS; CCDS6311.1; -. DR PIR; S40682; JN0708. DR RefSeq; NP_003292.1; NM_003301.7. DR PDB; 7WKD; EM; 3.01 A; R=1-398. DR PDB; 7X1T; EM; 3.26 A; A=1-398. DR PDB; 7X1U; EM; 3.19 A; A=1-398. DR PDB; 7XW9; EM; 2.70 A; R=1-398. DR AlphaFoldDB; P34981; -. DR EMDB; EMD-32565; -. DR EMDB; EMD-32949; -. DR EMDB; EMD-32950; -. DR EMDB; EMD-33494; -. DR SMR; P34981; -. DR BioGRID; 113052; 20. DR FunCoup; P34981; 867. DR IntAct; P34981; 18. DR NDEx; IQUERY-CP-TRHR; 3 NDEx IQuery Curated Pathways. DR STRING; 9606.ENSP00000430711; -. DR BindingDB; P34981; -. DR ChEMBL; CHEMBL1810; -. DR DrugBank; DB20206; Posatirelin. DR DrugBank; DB09421; Protirelin. DR DrugCentral; P34981; -. DR GuidetoPHARMACOLOGY; 363; -. DR TCDB; 9.A.14.1.4; the g-protein-coupled receptor (gpcr) family. DR GlyCosmos; P34981; 2 sites, No reported glycans. DR GlyGen; P34981; 2 sites. DR iPTMnet; P34981; -. DR PhosphoSitePlus; P34981; -. DR BioMuta; TRHR; -. DR DMDM; 464921; -. DR MassIVE; P34981; -. DR PaxDb; 9606-ENSP00000430711; -. DR PeptideAtlas; P34981; -. DR Antibodypedia; 13449; 304 antibodies from 33 providers. DR DNASU; 7201; -. DR Ensembl; ENST00000311762.2; ENSP00000309818.2; ENSG00000174417.3. DR Ensembl; ENST00000518632.2; ENSP00000430711.2; ENSG00000174417.3. DR GeneID; 7201; -. DR KEGG; hsa:7201; -. DR MANE-Select; ENST00000518632.2; ENSP00000430711.2; NM_003301.7; NP_003292.1. DR UCSC; uc003ymz.5; human. DR AGR; HGNC:12299; -. DR ClinPGx; PA36979; -. DR CTD; 7201; -. DR DisGeNET; 7201; -. DR GeneCards; TRHR; -. DR HGNC; HGNC:12299; TRHR. DR HPA; ENSG00000174417; Not detected. DR MalaCards; TRHR; -. DR MIM; 188545; gene. DR MIM; 618573; phenotype. DR OpenTargets; ENSG00000174417; -. DR Orphanet; 99832; Resistance to thyrotropin-releasing hormone syndrome. DR VEuPathDB; HostDB:ENSG00000174417; -. DR eggNOG; KOG3656; Eukaryota. DR GeneTree; ENSGT01150000286932; -. DR HOGENOM; CLU_009579_6_5_1; -. DR InParanoid; P34981; -. DR OMA; NCKQKPA; -. DR OrthoDB; 10036964at2759; -. DR PAN-GO; P34981; 2 GO annotations based on evolutionary models. DR PhylomeDB; P34981; -. DR PathwayCommons; P34981; -. DR Reactome; R-HSA-375276; Peptide ligand-binding receptors. DR Reactome; R-HSA-416476; G alpha (q) signalling events. DR SignaLink; P34981; -. DR SIGNOR; P34981; -. DR Agora; ENSG00000174417; -. DR BioGRID-ORCS; 7201; 9 hits in 1138 CRISPR screens. DR ChiTaRS; TRHR; human. DR GeneWiki; Thyrotropin-releasing_hormone_receptor; -. DR GenomeRNAi; 7201; -. DR Pharos; P34981; Tclin. DR PRO; PR:P34981; -. DR Proteomes; UP000005640; Chromosome 8. DR RNAct; P34981; protein. DR Bgee; ENSG00000174417; Expressed in male germ line stem cell (sensu Vertebrata) in testis and 13 other cell types or tissues. DR GO; GO:0005886; C:plasma membrane; EXP:UniProtKB. DR GO; GO:0004997; F:thyrotropin-releasing hormone receptor activity; IBA:GO_Central. DR GO; GO:0007186; P:G protein-coupled receptor signaling pathway; TAS:ProtInc. DR GO; GO:0007200; P:phospholipase C-activating G protein-coupled receptor signaling pathway; IBA:GO_Central. DR CDD; cd14995; 7tmA_TRH-R; 1. DR FunFam; 1.20.1070.10:FF:000186; thyrotropin-releasing hormone receptor; 1. DR Gene3D; 1.20.1070.10; Rhodopsin 7-helix transmembrane proteins; 1. DR InterPro; IPR000276; GPCR_Rhodpsn. DR InterPro; IPR017452; GPCR_Rhodpsn_7TM. DR InterPro; IPR002120; TRH_rcpt_1. DR PANTHER; PTHR46061; THYROTROPIN-RELEASING HORMONE RECEPTOR; 1. DR PANTHER; PTHR46061:SF2; THYROTROPIN-RELEASING HORMONE RECEPTOR; 1. DR Pfam; PF00001; 7tm_1; 1. DR PRINTS; PR00237; GPCRRHODOPSN. DR PRINTS; PR00751; THYROLIBRINR. DR PRINTS; PR01846; TRHRFAMILY. DR SMART; SM01381; 7TM_GPCR_Srsx; 1. DR SUPFAM; SSF81321; Family A G protein-coupled receptor-like; 1. DR PROSITE; PS00237; G_PROTEIN_RECEP_F1_1; 1. DR PROSITE; PS50262; G_PROTEIN_RECEP_F1_2; 1. DR PDBsum; 7WKD; -. DR PDBsum; 7X1T; -. DR PDBsum; 7X1U; -. DR PDBsum; 7XW9; -. PE 1: Evidence at protein level; KW 3D-structure; Cell membrane; Congenital hypothyroidism; Disease variant; KW Disulfide bond; G protein-coupled receptor; Glycoprotein; Membrane; KW Proteomics identification; Receptor; Reference proteome; Transducer; KW Transmembrane; Transmembrane helix. FT CHAIN 1..398 FT /note="Thyrotropin-releasing hormone receptor" FT /id="PRO_0000070187" FT TOPO_DOM 1..28 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 29..51 FT /note="Helical; Name=1" FT /evidence="ECO:0000255" FT TOPO_DOM 52..61 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 62..83 FT /note="Helical; Name=2" FT /evidence="ECO:0000255" FT TOPO_DOM 84..99 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 100..121 FT /note="Helical; Name=3" FT /evidence="ECO:0000255" FT TOPO_DOM 122..144 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 145..168 FT /note="Helical; Name=4" FT /evidence="ECO:0000255" FT TOPO_DOM 169..193 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 194..215 FT /note="Helical; Name=5" FT /evidence="ECO:0000255" FT TOPO_DOM 216..266 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 267..288 FT /note="Helical; Name=6" FT /evidence="ECO:0000255" FT TOPO_DOM 289..296 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 297..319 FT /note="Helical; Name=7" FT /evidence="ECO:0000255" FT TOPO_DOM 320..398 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT CARBOHYD 3 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 10 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT DISULFID 98..179 FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00521, FT ECO:0000269|PubMed:8770906" FT VARIANT 10 FT /note="N -> K (in dbSNP:rs5774)" FT /id="VAR_011857" FT VARIANT 17..398 FT /note="Missing (in CHNG7; loss of thyrotropin-releasing FT hormone receptor activity)" FT /evidence="ECO:0000269|PubMed:19213692, FT ECO:0000269|PubMed:9141550" FT /id="VAR_083281" FT VARIANT 81 FT /note="P -> R (in CHNG7; loss of thyrotropin-releasing FT hormone receptor activity; no effect on localization to FT plasma membrane)" FT /evidence="ECO:0000269|PubMed:26735259" FT /id="VAR_083282" FT VARIANT 115..118 FT /note="SITA -> T (in CHNG7; loss of thyrotropin-releasing FT hormone receptor activity)" FT /evidence="ECO:0000269|PubMed:9141550" FT /id="VAR_083283" FT VARIANT 131 FT /note="I -> T (in CHNG7; decreased affinity for TRH)" FT /evidence="ECO:0000269|PubMed:28419241" FT /id="VAR_083284" FT VARIANT 168 FT /note="I -> M (in dbSNP:rs13306060)" FT /id="VAR_049450" FT HELIX 24..52 FT /evidence="ECO:0007829|PDB:7XW9" FT STRAND 53..55 FT /evidence="ECO:0007829|PDB:7XW9" FT HELIX 59..74 FT /evidence="ECO:0007829|PDB:7XW9" FT HELIX 75..79 FT /evidence="ECO:0007829|PDB:7XW9" FT HELIX 80..88 FT /evidence="ECO:0007829|PDB:7XW9" FT HELIX 95..128 FT /evidence="ECO:0007829|PDB:7XW9" FT HELIX 130..136 FT /evidence="ECO:0007829|PDB:7XW9" FT HELIX 139..161 FT /evidence="ECO:0007829|PDB:7XW9" FT STRAND 164..168 FT /evidence="ECO:0007829|PDB:7XW9" FT STRAND 170..175 FT /evidence="ECO:0007829|PDB:7X1T" FT STRAND 177..183 FT /evidence="ECO:0007829|PDB:7XW9" FT HELIX 185..188 FT /evidence="ECO:0007829|PDB:7XW9" FT HELIX 189..196 FT /evidence="ECO:0007829|PDB:7XW9" FT HELIX 197..201 FT /evidence="ECO:0007829|PDB:7XW9" FT HELIX 202..219 FT /evidence="ECO:0007829|PDB:7XW9" FT HELIX 258..289 FT /evidence="ECO:0007829|PDB:7XW9" FT STRAND 292..294 FT /evidence="ECO:0007829|PDB:7XW9" FT TURN 298..300 FT /evidence="ECO:0007829|PDB:7XW9" FT HELIX 301..317 FT /evidence="ECO:0007829|PDB:7XW9" FT HELIX 318..322 FT /evidence="ECO:0007829|PDB:7XW9" FT HELIX 326..334 FT /evidence="ECO:0007829|PDB:7XW9" SQ SEQUENCE 398 AA; 45085 MW; FE920B5F2E933D3E CRC64; MENETVSELN QTQLQPRAVV ALEYQVVTIL LVLIICGLGI VGNIMVVLVV MRTKHMRTPT NCYLVSLAVA DLMVLVAAGL PNITDSIYGS WVYGYVGCLC ITYLQYLGIN ASSCSITAFT IERYIAICHP IKAQFLCTFS RAKKIIIFVW AFTSLYCMLW FFLLDLNIST YKDAIVISCG YKISRNYYSP IYLMDFGVFY VVPMILATVL YGFIARILFL NPIPSDPKEN SKTWKNDSTH QNTNLNVNTS NRCFNSTVSS RKQVTKMLAV VVILFALLWM PYRTLVVVNS FLSSPFQENW FLLFCRICIY LNSAINPVIY NLMSQKFRAA FRKLCNCKQK PTEKPANYSV ALNYSVIKES DHFSTELDDI TVTDTYLSAT KVSFDDTCLA SEVSFSQS //