NK3R_HUMAN
ID NK3R_HUMAN Reviewed; 465 AA.
AC P29371; Q0P510;
DT 01-DEC-1992, integrated into UniProtKB/Swiss-Prot.
DT 01-DEC-1992, sequence version 1.
DT 03-AUG-2022, entry version 176.
DE RecName: Full=Neuromedin-K receptor;
DE Short=NKR;
DE AltName: Full=NK-3 receptor;
DE Short=NK-3R;
DE AltName: Full=Neurokinin B receptor;
DE AltName: Full=Tachykinin receptor 3;
GN Name=TACR3; Synonyms=NK3R, TAC3R;
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].
RC TISSUE=Brain;
RX PubMed=1374246; DOI=10.1016/0006-291x(92)90685-e;
RA Huang R.-R.C., Cheung A.H., Mazina K.E., Strader C.D., Fong T.M.;
RT "cDNA sequence and heterologous expression of the human neurokinin-3
RT receptor.";
RL Biochem. Biophys. Res. Commun. 184:966-972(1992).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=1312036; DOI=10.1016/0014-5793(92)80107-r;
RA Buell G., Schulz M.F., Arkinstall S.J., Maury K., Missotten M., Adami N.,
RA Talabot F., Kawashima E.;
RT "Molecular characterisation, expression and localisation of human
RT neurokinin-3 receptor.";
RL FEBS Lett. 299:90-95(1992).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC TISSUE=Placenta;
RX PubMed=1312928; DOI=10.1111/j.1432-1033.1992.tb16724.x;
RA Takahashi K., Tanaka A., Hara M., Nakanishi S.;
RT "The primary structure and gene organization of human substance P and
RT neuromedin K receptors.";
RL Eur. J. Biochem. 204:1025-1033(1992).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain;
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 (NOV-2003) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
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 [6]
RP VARIANTS HH11 ASP-93 AND SER-353, AND CHARACTERIZATION OF VARIANTS HH11
RP ASP-93 AND SER-353.
RX PubMed=19079066; DOI=10.1038/ng.306;
RA Topaloglu A.K., Reimann F., Guclu M., Yalin A.S., Kotan L.D., Porter K.M.,
RA Serin A., Mungan N.O., Cook J.R., Ozbek M.N., Imamoglu S., Akalin N.S.,
RA Yuksel B., O'Rahilly S., Semple R.K.;
RT "TAC3 and TACR3 mutations in familial hypogonadotropic hypogonadism reveal
RT a key role for Neurokinin B in the central control of reproduction.";
RL Nat. Genet. 41:354-358(2009).
RN [7]
RP VARIANT HH11 GLN-364, AND VARIANTS ARG-286 AND THR-449.
RX PubMed=23643382; DOI=10.1016/j.ajhg.2013.04.008;
RA Miraoui H., Dwyer A.A., Sykiotis G.P., Plummer L., Chung W., Feng B.,
RA Beenken A., Clarke J., Pers T.H., Dworzynski P., Keefe K., Niedziela M.,
RA Raivio T., Crowley W.F. Jr., Seminara S.B., Quinton R., Hughes V.A.,
RA Kumanov P., Young J., Yialamas M.A., Hall J.E., Van Vliet G.,
RA Chanoine J.P., Rubenstein J., Mohammadi M., Tsai P.S., Sidis Y., Lage K.,
RA Pitteloud N.;
RT "Mutations in FGF17, IL17RD, DUSP6, SPRY4, and FLRT3 are identified in
RT individuals with congenital hypogonadotropic hypogonadism.";
RL Am. J. Hum. Genet. 92:725-743(2013).
RN [8]
RP VARIANTS HH11 VAL-137 AND VAL-346.
RX PubMed=25077900; DOI=10.1210/jc.2014-2110;
RA Marcos S., Sarfati J., Leroy C., Fouveaut C., Parent P., Metz C.,
RA Wolczynski S., Gerard M., Bieth E., Kurtz F., Verier-Mine O., Perrin L.,
RA Archambeaud F., Cabrol S., Rodien P., Hove H., Prescott T., Lacombe D.,
RA Christin-Maitre S., Touraine P., Hieronimus S., Dewailly D., Young J.,
RA Pugeat M., Hardelin J.P., Dode C.;
RT "The prevalence of CHD7 missense versus truncating mutations is higher in
RT patients with Kallmann syndrome than in typical CHARGE patients.";
RL J. Clin. Endocrinol. Metab. 99:E2138-2143(2014).
CC -!- FUNCTION: This is a receptor for the tachykinin neuropeptide
CC neuromedin-K (neurokinin B). It is associated with G proteins that
CC activate a phosphatidylinositol-calcium second messenger system. The
CC rank order of affinity of this receptor to tachykinins is: neuromedin-K
CC > substance K > substance P.
CC -!- INTERACTION:
CC P29371; PRO_0000033566 [Q9UHF0]: TAC3; NbExp=2; IntAct=EBI-6655576, EBI-6655626;
CC -!- SUBCELLULAR LOCATION: Cell membrane; Multi-pass membrane protein.
CC -!- PTM: The anchoring of this receptor to the plasma membrane is probably
CC mediated by the palmitoylation of a cysteine residue.
CC -!- DISEASE: Hypogonadotropic hypogonadism 11 with or without anosmia
CC (HH11) [MIM:614840]: A disorder characterized by absent or incomplete
CC sexual maturation by the age of 18 years, in conjunction with low
CC levels of circulating gonadotropins and testosterone and no other
CC abnormalities of the hypothalamic-pituitary axis. In some cases, it is
CC associated with non-reproductive phenotypes, such as anosmia, cleft
CC palate, and sensorineural hearing loss. Anosmia or hyposmia is related
CC to the absence or hypoplasia of the olfactory bulbs and tracts.
CC Hypogonadism is due to deficiency in gonadotropin-releasing hormone and
CC probably results from a failure of embryonic migration of gonadotropin-
CC releasing hormone-synthesizing neurons. In the presence of anosmia,
CC idiopathic hypogonadotropic hypogonadism is referred to as Kallmann
CC syndrome, whereas in the presence of a normal sense of smell, it has
CC been termed normosmic idiopathic hypogonadotropic hypogonadism (nIHH).
CC {ECO:0000269|PubMed:19079066, ECO:0000269|PubMed:23643382,
CC ECO:0000269|PubMed:25077900}. Note=The disease is caused by variants
CC affecting distinct genetic loci, including the gene represented in this
CC entry. The genetics of hypogonadotropic hypogonadism involves various
CC modes of transmission. Oligogenic inheritance has been reported in some
CC patients carrying mutations in TACR3 as well as in other HH-associated
CC genes including FGFR1, SPRY4 and KAL1 (PubMed:23643382).
CC {ECO:0000269|PubMed:23643382}.
CC -!- SIMILARITY: Belongs to the G-protein coupled receptor 1 family.
CC {ECO:0000255|PROSITE-ProRule:PRU00521}.
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DR EMBL; M89473; AAA36366.1; -; mRNA.
DR EMBL; S86392; AAB21706.1; -; Genomic_DNA.
DR EMBL; S86371; AAB21706.1; JOINED; Genomic_DNA.
DR EMBL; S86382; AAB21706.1; JOINED; Genomic_DNA.
DR EMBL; S86388; AAB21706.1; JOINED; Genomic_DNA.
DR EMBL; S86390; AAB21706.1; JOINED; Genomic_DNA.
DR EMBL; X65172; CAA46291.1; -; Genomic_DNA.
DR EMBL; X65173; CAA46291.1; JOINED; Genomic_DNA.
DR EMBL; X65174; CAA46291.1; JOINED; Genomic_DNA.
DR EMBL; X65175; CAA46291.1; JOINED; Genomic_DNA.
DR EMBL; X65176; CAA46291.1; JOINED; Genomic_DNA.
DR EMBL; AY462099; AAR23926.1; -; mRNA.
DR EMBL; BC121806; AAI21807.1; -; mRNA.
DR CCDS; CCDS3664.1; -.
DR PIR; JQ1517; JQ1517.
DR RefSeq; NP_001050.1; NM_001059.2.
DR AlphaFoldDB; P29371; -.
DR SMR; P29371; -.
DR BioGRID; 112733; 72.
DR IntAct; P29371; 1.
DR STRING; 9606.ENSP00000303325; -.
DR BindingDB; P29371; -.
DR ChEMBL; CHEMBL4429; -.
DR DrugBank; DB04872; Osanetant.
DR DrugBank; DB11692; Pavinetant.
DR DrugBank; DB06429; Talnetant.
DR DrugCentral; P29371; -.
DR GuidetoPHARMACOLOGY; 362; -.
DR GlyGen; P29371; 3 sites.
DR iPTMnet; P29371; -.
DR PhosphoSitePlus; P29371; -.
DR BioMuta; TACR3; -.
DR DMDM; 128364; -.
DR PaxDb; P29371; -.
DR PeptideAtlas; P29371; -.
DR PRIDE; P29371; -.
DR TopDownProteomics; P29371; -.
DR Antibodypedia; 1543; 370 antibodies from 34 providers.
DR DNASU; 6870; -.
DR Ensembl; ENST00000304883.3; ENSP00000303325.2; ENSG00000169836.5.
DR GeneID; 6870; -.
DR KEGG; hsa:6870; -.
DR MANE-Select; ENST00000304883.3; ENSP00000303325.2; NM_001059.3; NP_001050.1.
DR UCSC; uc003hxe.2; human.
DR CTD; 6870; -.
DR DisGeNET; 6870; -.
DR GeneCards; TACR3; -.
DR GeneReviews; TACR3; -.
DR HGNC; HGNC:11528; TACR3.
DR HPA; ENSG00000169836; Group enriched (brain, retina, urinary bladder).
DR MalaCards; TACR3; -.
DR MIM; 162332; gene.
DR MIM; 614840; phenotype.
DR neXtProt; NX_P29371; -.
DR OpenTargets; ENSG00000169836; -.
DR Orphanet; 478; Kallmann syndrome.
DR Orphanet; 432; Normosmic congenital hypogonadotropic hypogonadism.
DR PharmGKB; PA36304; -.
DR VEuPathDB; HostDB:ENSG00000169836; -.
DR eggNOG; KOG4219; Eukaryota.
DR GeneTree; ENSGT00940000153745; -.
DR HOGENOM; CLU_009579_6_1_1; -.
DR InParanoid; P29371; -.
DR OMA; PQCLYSI; -.
DR OrthoDB; 715197at2759; -.
DR PhylomeDB; P29371; -.
DR TreeFam; TF315303; -.
DR PathwayCommons; P29371; -.
DR Reactome; R-HSA-380095; Tachykinin receptors bind tachykinins.
DR Reactome; R-HSA-416476; G alpha (q) signalling events.
DR SignaLink; P29371; -.
DR SIGNOR; P29371; -.
DR BioGRID-ORCS; 6870; 6 hits in 1071 CRISPR screens.
DR ChiTaRS; TACR3; human.
DR GeneWiki; Tachykinin_receptor_3; -.
DR GenomeRNAi; 6870; -.
DR Pharos; P29371; Tchem.
DR PRO; PR:P29371; -.
DR Proteomes; UP000005640; Chromosome 4.
DR RNAct; P29371; protein.
DR Bgee; ENSG00000169836; Expressed in cortical plate and 31 other tissues.
DR Genevisible; P29371; HS.
DR GO; GO:0005737; C:cytoplasm; IEA:Ensembl.
DR GO; GO:0032590; C:dendrite membrane; IEA:Ensembl.
DR GO; GO:0005887; C:integral component of plasma membrane; TAS:ProtInc.
DR GO; GO:0032809; C:neuronal cell body membrane; IEA:Ensembl.
DR GO; GO:0005634; C:nucleus; IEA:Ensembl.
DR GO; GO:0005886; C:plasma membrane; IBA:GO_Central.
DR GO; GO:0097225; C:sperm midpiece; IDA:UniProtKB.
DR GO; GO:0004995; F:tachykinin receptor activity; IBA:GO_Central.
DR GO; GO:0007568; P:aging; IEA:Ensembl.
DR GO; GO:0042538; P:hyperosmotic salinity response; IEA:Ensembl.
DR GO; GO:0045777; P:positive regulation of blood pressure; IEA:Ensembl.
DR GO; GO:1902093; P:positive regulation of flagellated sperm motility; IMP:UniProtKB.
DR GO; GO:0010460; P:positive regulation of heart rate; IEA:Ensembl.
DR GO; GO:0070474; P:positive regulation of uterine smooth muscle contraction; IEA:Ensembl.
DR GO; GO:0042053; P:regulation of dopamine metabolic process; IEA:Ensembl.
DR GO; GO:0060259; P:regulation of feeding behavior; IEA:Ensembl.
DR GO; GO:0042220; P:response to cocaine; IEA:Ensembl.
DR GO; GO:0032355; P:response to estradiol; IEA:Ensembl.
DR GO; GO:0043278; P:response to morphine; IEA:Ensembl.
DR GO; GO:0007217; P:tachykinin receptor signaling pathway; TAS:ProtInc.
DR InterPro; IPR000276; GPCR_Rhodpsn.
DR InterPro; IPR017452; GPCR_Rhodpsn_7TM.
DR InterPro; IPR001681; Neurokn_rcpt.
DR InterPro; IPR001013; NK3_rcpt.
DR Pfam; PF00001; 7tm_1; 1.
DR PRINTS; PR00237; GPCRRHODOPSN.
DR PRINTS; PR01026; NEUROKININ3R.
DR PRINTS; PR00244; NEUROKININR.
DR PROSITE; PS00237; G_PROTEIN_RECEP_F1_1; 1.
DR PROSITE; PS50262; G_PROTEIN_RECEP_F1_2; 1.
PE 1: Evidence at protein level;
KW Cell membrane; Disease variant; Disulfide bond; G-protein coupled receptor;
KW Glycoprotein; Hypogonadotropic hypogonadism; Lipoprotein; Membrane;
KW Palmitate; Receptor; Reference proteome; Transducer; Transmembrane;
KW Transmembrane helix.
FT CHAIN 1..465
FT /note="Neuromedin-K receptor"
FT /id="PRO_0000069899"
FT TOPO_DOM 1..84
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 85..107
FT /note="Helical; Name=1"
FT /evidence="ECO:0000255"
FT TOPO_DOM 108..117
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 118..139
FT /note="Helical; Name=2"
FT /evidence="ECO:0000255"
FT TOPO_DOM 140..159
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 160..181
FT /note="Helical; Name=3"
FT /evidence="ECO:0000255"
FT TOPO_DOM 182..201
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 202..222
FT /note="Helical; Name=4"
FT /evidence="ECO:0000255"
FT TOPO_DOM 223..245
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 246..270
FT /note="Helical; Name=5"
FT /evidence="ECO:0000255"
FT TOPO_DOM 271..299
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 300..321
FT /note="Helical; Name=6"
FT /evidence="ECO:0000255"
FT TOPO_DOM 322..334
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 335..359
FT /note="Helical; Name=7"
FT /evidence="ECO:0000255"
FT TOPO_DOM 360..465
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT REGION 415..465
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 436..465
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT LIPID 374
FT /note="S-palmitoyl cysteine"
FT /evidence="ECO:0000255"
FT CARBOHYD 23
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 50
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 73
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 158..233
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00521"
FT VARIANT 93
FT /note="G -> D (in HH11; unequivocal evidence of impaired
FT receptor signaling; dbSNP:rs121918124)"
FT /evidence="ECO:0000269|PubMed:19079066"
FT /id="VAR_069177"
FT VARIANT 137
FT /note="F -> V (in HH11)"
FT /evidence="ECO:0000269|PubMed:25077900"
FT /id="VAR_072976"
FT VARIANT 286
FT /note="K -> R (may contribute to hypogonadotropic
FT hypogonadism in patients carrying disease-causing mutations
FT in FGFR1; dbSNP:rs2276973)"
FT /evidence="ECO:0000269|PubMed:23643382"
FT /id="VAR_049422"
FT VARIANT 346
FT /note="M -> V (in HH11; dbSNP:rs200148989)"
FT /evidence="ECO:0000269|PubMed:25077900"
FT /id="VAR_072977"
FT VARIANT 353
FT /note="P -> S (in HH11; unequivocal evidence of impaired
FT receptor signaling; dbSNP:rs121918125)"
FT /evidence="ECO:0000269|PubMed:19079066"
FT /id="VAR_069178"
FT VARIANT 364
FT /note="R -> Q (in HH11; the patient also carries a mutation
FT in FGFR1; dbSNP:rs150288991)"
FT /evidence="ECO:0000269|PubMed:23643382"
FT /id="VAR_069963"
FT VARIANT 449
FT /note="A -> T (may contribute to hypogonadotropic
FT hypogonadism in patients carrying disease-causing mutations
FT in SPRY4 or KAL1; dbSNP:rs17033889)"
FT /evidence="ECO:0000269|PubMed:23643382"
FT /id="VAR_049423"
FT CONFLICT 3
FT /note="T -> I (in Ref. 2; AAB21706)"
FT /evidence="ECO:0000305"
FT CONFLICT 63
FT /note="A -> R (in Ref. 2; AAB21706)"
FT /evidence="ECO:0000305"
FT CONFLICT 439
FT /note="C -> F (in Ref. 3; CAA46291)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 465 AA; 52202 MW; 98E88D4BC9DBD315 CRC64;
MATLPAAETW IDGGGGVGAD AVNLTASLAA GAATGAVETG WLQLLDQAGN LSSSPSALGL
PVASPAPSQP WANLTNQFVQ PSWRIALWSL AYGVVVAVAV LGNLIVIWII LAHKRMRTVT
NYFLVNLAFS DASMAAFNTL VNFIYALHSE WYFGANYCRF QNFFPITAVF ASIYSMTAIA
VDRYMAIIDP LKPRLSATAT KIVIGSIWIL AFLLAFPQCL YSKTKVMPGR TLCFVQWPEG
PKQHFTYHII VIILVYCFPL LIMGITYTIV GITLWGGEIP GDTCDKYHEQ LKAKRKVVKM
MIIVVMTFAI CWLPYHIYFI LTAIYQQLNR WKYIQQVYLA SFWLAMSSTM YNPIIYCCLN
KRFRAGFKRA FRWCPFIKVS SYDELELKTT RFHPNRQSSM YTVTRMESMT VVFDPNDADT
TRSSRKKRAT PRDPSFNGCS RRNSKSASAT SSFISSPYTS VDEYS
