ID KISSR_HUMAN Reviewed; 398 AA. AC Q969F8; A5D8U2; B2RTV1; Q96QG0; DT 01-MAR-2005, integrated into UniProtKB/Swiss-Prot. DT 06-FEB-2007, sequence version 2. DT 02-SEP-2026, entry version 185. DE RecName: Full=KiSS-1 receptor; DE Short=KiSS-1R; DE AltName: Full=G protein-coupled receptor 54; DE AltName: Full=G protein-coupled receptor OT7T175; DE Short=hOT7T175; DE AltName: Full=Hypogonadotropin-1; DE AltName: Full=Kisspeptins receptor; DE AltName: Full=Metastin receptor; GN Name=KISS1R; Synonyms=AXOR12 {ECO:0000303|PubMed:11387329}, GPR54; 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], VARIANT HIS-364, AND TISSUE SPECIFICITY. RX PubMed=11385580; DOI=10.1038/35079135; RA Ohtaki T., Shintani Y., Honda S., Matsumoto H., Hori A., Kanehashi K., RA Terao Y., Kumano S., Takatsu Y., Masuda Y., Ishibashi Y., Watanabe T., RA Asada M., Yamada T., Suenaga M., Kitada C., Usuki S., Kurokawa T., Onda H., RA Nishimura O., Fujino M.; RT "Metastasis suppressor gene KiSS-1 encodes peptide ligand of a G-protein- RT coupled receptor."; RL Nature 411:613-617(2001). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA], VARIANT HIS-364, AND TISSUE SPECIFICITY. RX PubMed=11414709; DOI=10.1006/bbrc.2001.5098; RA Clements M.K., McDonald T.P., Wang R., Xie G., O'Dowd B.F., George S.R., RA Austin C.P., Liu Q.; RT "FMRFamide-related neuropeptides are agonists of the orphan G-protein- RT coupled receptor GPR54."; RL Biochem. Biophys. Res. Commun. 284:1189-1193(2001). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA], AND TISSUE SPECIFICITY. RC TISSUE=Brain; RX PubMed=11387329; DOI=10.1074/jbc.m102743200; RA Muir A.I., Chamberlain L., Elshourbagy N.A., Michalovich D., Moore D.J., RA Calamari A., Szekeres P.G., Sarau H.M., Chambers J.K., Murdock P., RA Steplewski K., Shabon U., Miller J.E., Middleton S.E., Darker J.G., RA Larminie C.G.C., Wilson S., Bergsma D.J., Emson P., Faull R., RA Philpott K.L., Harrison D.C.; RT "AXOR12, a novel human G protein-coupled receptor, activated by the peptide RT KiSS-1."; RL J. Biol. Chem. 276:28969-28975(2001). RN [4] RP NUCLEOTIDE SEQUENCE [MRNA], VARIANT HIS-364, FUNCTION, AND TISSUE RP SPECIFICITY. RC TISSUE=Hypothalamus; RX PubMed=11457843; DOI=10.1074/jbc.m104847200; RA Kotani M., Detheux M., Vandenbogaerde A., Communi D., Vanderwinden J.-M., RA Le Poul E., Brezillon S., Tyldesley R., Suarez-Huerta N., Vandeput F., RA Blanpain C., Schiffmann S.N., Vassart G., Parmentier M.; RT "The metastasis suppressor gene KiSS-1 encodes kisspeptins, the natural RT ligands of the orphan G protein-coupled receptor GPR54."; RL J. Biol. Chem. 276:34631-34636(2001). RN [5] RP NUCLEOTIDE SEQUENCE [MRNA], VARIANT HH8 SER-148, VARIANT HIS-364, FUNCTION, RP AND CHARACTERIZATION OF VARIANT HH8 SER-148. RX PubMed=14573733; DOI=10.1056/nejmoa035322; RA Seminara S.B., Messager S., Chatzidaki E.E., Thresher R.R., RA Acierno J.S. Jr., Shagoury J.K., Bo-Abbas Y., Kuohung W., Schwinof K.M., RA Hendrick A.G., Zahn D., Dixon J., Kaiser U.B., Slaugenhaupt S.A., RA Gusella J.F., O'Rahilly S., Carlton M.B.L., Crowley W.F. Jr., RA Aparicio S.A.J.R., Colledge W.H.; RT "The GPR54 gene as a regulator of puberty."; RL N. Engl. J. Med. 349:1614-1627(2003). RN [6] RP NUCLEOTIDE SEQUENCE [MRNA]. RC TISSUE=Kidney; RA Kaighin V.A., Martin A.L., Aronstam R.S.; RT "Isolation of cDNA coding for human KISS1 receptor (KISS1R)."; RL Submitted (JUL-2008) to the EMBL/GenBank/DDBJ databases. RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15057824; DOI=10.1038/nature02399; RA Grimwood J., Gordon L.A., Olsen A.S., Terry A., Schmutz J., Lamerdin J.E., RA Hellsten U., Goodstein D., Couronne O., Tran-Gyamfi M., Aerts A., RA Altherr M., Ashworth L., Bajorek E., Black S., Branscomb E., Caenepeel S., RA Carrano A.V., Caoile C., Chan Y.M., Christensen M., Cleland C.A., RA Copeland A., Dalin E., Dehal P., Denys M., Detter J.C., Escobar J., RA Flowers D., Fotopulos D., Garcia C., Georgescu A.M., Glavina T., Gomez M., RA Gonzales E., Groza M., Hammon N., Hawkins T., Haydu L., Ho I., Huang W., RA Israni S., Jett J., Kadner K., Kimball H., Kobayashi A., Larionov V., RA Leem S.-H., Lopez F., Lou Y., Lowry S., Malfatti S., Martinez D., RA McCready P.M., Medina C., Morgan J., Nelson K., Nolan M., Ovcharenko I., RA Pitluck S., Pollard M., Popkie A.P., Predki P., Quan G., Ramirez L., RA Rash S., Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A., RA She X., Smith D., Slezak T., Solovyev V., Thayer N., Tice H., Tsai M., RA Ustaszewska A., Vo N., Wagner M., Wheeler J., Wu K., Xie G., Yang J., RA Dubchak I., Furey T.S., DeJong P., Dickson M., Gordon D., Eichler E.E., RA Pennacchio L.A., Richardson P., Stubbs L., Rokhsar D.S., Myers R.M., RA Rubin E.M., Lucas S.M.; RT "The DNA sequence and biology of human chromosome 19."; RL Nature 428:529-535(2004). RN [8] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], AND VARIANT HIS-364. 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 [9] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT HIS-364. 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 [10] RP REVIEW. RX PubMed=15519892; DOI=10.1016/j.tem.2004.09.008; RA Colledge W.H.; RT "GPR54 and puberty."; RL Trends Endocrinol. Metab. 15:448-453(2004). RN [11] RP FUNCTION. RX PubMed=11527393; DOI=10.1006/bbrc.2001.5470; RA Hori A., Honda S., Asada M., Ohtaki T., Oda K., Watanabe T., Shintani Y., RA Yamada T., Suenaga M., Kitada C., Onda H., Kurokawa T., Nishimura O., RA Fujino M.; RT "Metastin suppresses the motility and growth of CHO cells transfected with RT its receptor."; RL Biochem. Biophys. Res. Commun. 286:958-963(2001). RN [12] RP TISSUE SPECIFICITY. RX PubMed=12414911; DOI=10.1210/jc.2002-021093; RA Janneau J.-L., Maldonado-Estrada J., Tachdjian G., Miran I., Motte N., RA Saulnier P., Sabourin J.-C., Cote J.-F., Simon B., Frydman R., Chaouat G., RA Bellet D.; RT "Transcriptional expression of genes involved in cell invasion and RT migration by normal and tumoral trophoblast cells."; RL J. Clin. Endocrinol. Metab. 87:5336-5339(2002). RN [13] RP INVOLVEMENT IN HH8, AND FUNCTION. RX PubMed=12944565; DOI=10.1073/pnas.1834399100; RA de Roux N., Genin E., Carel J.-C., Matsuda F., Chaussain J.-L., Milgrom E.; RT "Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived RT peptide receptor GPR54."; RL Proc. Natl. Acad. Sci. U.S.A. 100:10972-10976(2003). RN [14] RP TISSUE SPECIFICITY, AND FUNCTION. RX PubMed=15020672; DOI=10.1242/jcs.00971; RA Bilban M., Ghaffari-Tabrizi N., Hintermann E., Bauer S., Molzer S., RA Zoratti C., Malli R., Sharabi A., Hiden U., Graier W., Knoefler M., RA Andreae F., Wagner O., Quaranta V., Desoye G.; RT "Kisspeptin-10, a KiSS-1/metastin-derived decapeptide, is a physiological RT invasion inhibitor of primary human trophoblasts."; RL J. Cell Sci. 117:1319-1328(2004). RN [15] RP FUNCTION. RX PubMed=15596153; DOI=10.1016/j.bbrc.2004.11.094; RA Becker J.A.J., Mirjolet J.-F., Bernard J., Burgeon E., Simons M.-J., RA Vassart G., Parmentier M., Libert F.; RT "Activation of GPR54 promotes cell cycle arrest and apoptosis of human RT tumor cells through a specific transcriptional program not shared by other RT G(q)-coupled receptors."; RL Biochem. Biophys. Res. Commun. 326:677-686(2005). RN [16] RP SUBCELLULAR LOCATION, CHARACTERIZATION OF VARIANT HH8 SER-148, AND RP MUTAGENESIS OF LEU-148. RX PubMed=18772143; DOI=10.1074/jbc.m805251200; RA Wacker J.L., Feller D.B., Tang X.B., Defino M.C., Namkung Y., Lyssand J.S., RA Mhyre A.J., Tan X., Jensen J.B., Hague C.; RT "Disease-causing mutation in GPR54 reveals the importance of the second RT intracellular loop for class A G-protein-coupled receptor function."; RL J. Biol. Chem. 283:31068-31078(2008). RN [17] RP FUNCTION, AND CHARACTERIZATION OF VARIANT HH8 SER-148. RX PubMed=25147978; DOI=10.1210/en.2014-1304; RA Ahow M., Min L., Pampillo M., Nash C., Wen J., Soltis K., Carroll R.S., RA Glidewell-Kenney C.A., Mellon P.L., Bhattacharya M., Tobet S.A., RA Kaiser U.B., Babwah A.V.; RT "KISS1R signals independently of Galphaq/11 and triggers LH secretion via RT the beta-arrestin pathway in the male mouse."; RL Endocrinology 155:4433-4446(2014). RN [18] RP FUNCTION. RX PubMed=38512807; DOI=10.1165/rcmb.2023-0469oc; RA Balraj P., Ambhore N.S., Ramakrishnan Y.S., Borkar N.A., Banerjee P., RA Reza M.I., Varadharajan S., Kumar A., Pabelick C.M., Prakash Y.S., RA Sathish V.; RT "Kisspeptin/KISS1R Signaling Modulates Human Airway Smooth Muscle Cell RT Migration."; RL Am. J. Respir. Cell Mol. Biol. 70:507-518(2024). RN [19] {ECO:0007744|PDB:8ZJD, ECO:0007744|PDB:8ZJE} RP STRUCTURE BY ELECTRON MICROSCOPY (3.06 ANGSTROMS) OF 2-355 IN COMPLEX WITH RP AGONISTS AND G PROTEINS, AND DISULFIDE BONDS. RX PubMed=38935498; DOI=10.1016/j.celrep.2024.114389; RA Shen S., Wang D., Liu H., He X., Cao Y., Chen J., Li S., Cheng X., Xu H.E., RA Duan J.; RT "Structural basis for hormone recognition and distinctive Gq protein RT coupling by the kisspeptin receptor."; RL Cell Rep. 43:114389-114389(2024). RN [20] {ECO:0007744|PDB:7YQE} RP X-RAY CRYSTALLOGRAPHY (3.50 ANGSTROMS) OF 333-357 IN COMPLEX WITH SRC, RP FUNCTION, INTERACTION WITH SRC AND DUSP18, AND MUTAGENESIS OF ARG-336 AND RP PRO-339. RX PubMed=38346942; DOI=10.1038/s41467-024-44852-9; RA Li Z., Yang X., Fu R., Wu Z., Xu S., Jiao J., Qian M., Zhang L., Wu C., RA Xie T., Yao J., Wu Z., Li W., Ma G., You Y., Chen Y., Zhang H.K., Cheng Y., RA Tang X., Wu P., Lian G., Wei H., Zhao J., Xu J., Ai L., Siwko S., Wang Y., RA Ding J., Song G., Luo J., Liu M., Xiao J.; RT "Kisspeptin-10 binding to Gpr54 in osteoclasts prevents bone loss by RT activating Dusp18-mediated dephosphorylation of Src."; RL Nat. Commun. 15:1300-1300(2024). RN [21] RP ERRATUM OF PUBMED:38346942. RX PubMed=39702286; DOI=10.1038/s41467-024-55352-1; RA Li Z., Yang X., Fu R., Wu Z., Xu S., Jiao J., Qian M., Zhang L., Wu C., RA Xie T., Yao J., Wu Z., Li W., Ma G., You Y., Chen Y., Zhang H.K., Cheng Y., RA Tang X., Wu P., Lian G., Wei H., Zhao J., Xu J., Ai L., Siwko S., Wang Y., RA Ding J., Song G., Luo J., Liu M., Xiao J.; RL Nat. Commun. 15:10696-10696(2024). RN [22] {ECO:0007744|PDB:8XGO, ECO:0007744|PDB:8XGS, ECO:0007744|PDB:8XGU} RP STRUCTURE BY ELECTRON MICROSCOPY (2.68 ANGSTROMS) IN COMPLEX WITH AGONISTS RP AND G PROTEINS, DISULFIDE BONDS, FUNCTION, AND MUTAGENESIS OF THR-99; RP ASN-119; GLN-122; GLN-123; HIS-181; GLU-193; ARG-297; TYR-302; LYS-305; RP HIS-309 AND TYR-313. RX PubMed=39151001; DOI=10.1126/sciadv.adn7771; RA Wu Z., Chen G., Qiu C., Yan X., Xu L., Jiang S., Xu J., Han R., Shi T., RA Liu Y., Gao W., Wang Q., Li J., Ye F., Pan X., Zhang Z., Ning P., Zhang B., RA Chen J., Du Y.; RT "Structural basis for the ligand recognition and G protein subtype RT selectivity of kisspeptin receptor."; RL Sci. Adv. 10:eadn7771-eadn7771(2024). RN [23] RP VARIANTS HH8 ARG-223 AND LEU-297, VARIANT HIS-364, CHARACTERIZATION OF RP VARIANTS HH8 ARG-223 AND LEU-297, AND FUNCTION. RX PubMed=15598687; DOI=10.1210/jc.2004-1418; RA Semple R.K., Achermann J.C., Ellery J., Farooqi I.S., Karet F.E., RA Stanhope R.G., O'rahilly S., Aparicio S.A.; RT "Two novel missense mutations in G protein-coupled receptor 54 in a patient RT with hypogonadotropic hypogonadism."; RL J. Clin. Endocrinol. Metab. 90:1849-1855(2005). RN [24] RP VARIANT HH8 PRO-102, AND FUNCTION. RX PubMed=17164310; DOI=10.1210/jc.2006-2147; RA Tenenbaum-Rakover Y., Commenges-Ducos M., Iovane A., Aumas C., Admoni O., RA de Roux N.; RT "Neuroendocrine phenotype analysis in five patients with isolated RT hypogonadotropic hypogonadism due to a L102P inactivating mutation of RT GPR54."; RL J. Clin. Endocrinol. Metab. 92:1137-1144(2007). RN [25] RP VARIANT CPPB1 PRO-386, CHARACTERIZATION OF VARIANT CPPB1 PRO-386, AND RP FUNCTION. RX PubMed=18272894; DOI=10.1056/nejmoa073443; RA Teles M.G., Bianco S.D.C., Brito V.N., Trarbach E.B., Kuohung W., Xu S., RA Seminara S.B., Mendonca B.B., Kaiser U.B., Latronico A.C.; RT "A GPR54-activating mutation in a patient with central precocious RT puberty."; RL N. Engl. J. Med. 358:709-715(2008). RN [26] RP VARIANTS HH8 THR-189 AND ASP-194. 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 [27] RP VARIANT HH8 LEU-262. 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: Receptor for kisspeptins (kisspeptin-10, kisspeptin-13, CC kisspeptin-14 and metastin/kisspeptin-54) (PubMed:11457843, CC PubMed:11527393, PubMed:15020672, PubMed:15596153). The hypothalamic CC KISS1/KISS1R signaling system plays a central role in the regulation of CC the hypothalamic-pituitary-gonadal reproductive axis by modulating the CC secretion of gonadotropin-releasing hormone (GnRH) from GnRH neurons CC (PubMed:12944565, PubMed:14573733, PubMed:15598687, PubMed:17164310, CC PubMed:18272894). In these neurons, kisspeptin binding to its receptor CC activates G(q)-dependent signaling, leading to phospholipase C (PLC) CC activation, and hydrolysis of phosphatidylinositol 4,5-bisphosphate CC (PIP2) (PubMed:14573733, PubMed:15598687, PubMed:39151001). The CC subsequent rise in intracellular calcium levels results in the CC inhibition of inward rectifier potassium channels and activation of CC TRPC-like cation channels, leading to GnRH neurons depolarization and CC stimulation (By similarity). In addition to this pathway, kisspeptin CC also triggers G(q)-independent signaling via beta-arrestin, leading to CC MAPK cascade activation and ERK1/ERK2 phosphorylation CC (PubMed:25147978). Furthermore, activation of KISS1R by kisspeptin-10 CC recruits phosphatase DUSP18 and SRC to the KISS1R C-terminus through a CC G(q)-dependent signaling pathway, leading to DUSP18-mediated CC dephosphorylation of SRC (PubMed:38346942). In bone tissue, this CC results in down-regulation of osteoclast differentiation and activity, CC and consequently suppression of bone resorption (By similarity). KISS1R CC is also involved in the regulation of other processes, including cell CC proliferation and cell migration (PubMed:11457843, PubMed:11527393, CC PubMed:15020672, PubMed:15596153, PubMed:38512807). CC {ECO:0000250|UniProtKB:Q91V45, ECO:0000269|PubMed:11457843, CC ECO:0000269|PubMed:11527393, ECO:0000269|PubMed:12944565, CC ECO:0000269|PubMed:14573733, ECO:0000269|PubMed:15020672, CC ECO:0000269|PubMed:15596153, ECO:0000269|PubMed:15598687, CC ECO:0000269|PubMed:17164310, ECO:0000269|PubMed:18272894, CC ECO:0000269|PubMed:25147978, ECO:0000269|PubMed:38346942, CC ECO:0000269|PubMed:38512807, ECO:0000269|PubMed:39151001}. CC -!- SUBUNIT: Interacts with SRC and DUSP18; the interaction depends on CC receptor activation by kisspeptin-10 and is required for DUSP18- CC mediated dephosphorylation of SRC (PubMed:38346942). Interaction with CC SRC and DUSP18 is relevant for down-regulation of osteoclast CC differentiation and activity, and consequently suppression of bone CC resorption (By similarity). {ECO:0000250|UniProtKB:Q91V45, CC ECO:0000269|PubMed:38346942}. CC -!- INTERACTION: CC Q969F8; P50148: GNAQ; NbExp=2; IntAct=EBI-8481408, EBI-3909604; CC Q969F8; P67775: PPP2CA; NbExp=3; IntAct=EBI-8481408, EBI-712311; CC Q969F8; O60894: RAMP1; NbExp=2; IntAct=EBI-8481408, EBI-962893; CC Q969F8; O60895: RAMP2; NbExp=3; IntAct=EBI-8481408, EBI-9009040; CC Q969F8; O60896: RAMP3; NbExp=3; IntAct=EBI-8481408, EBI-720447; CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:18772143}; CC Multi-pass membrane protein {ECO:0000255}. CC -!- TISSUE SPECIFICITY: Expressed in the pancreas, placenta and spinal CC cord, with lower-level of expression in peripheral blood leukocytes, CC kidney, lung, fetal liver, stomach, small intestine, testes, spleen, CC thymus, adrenal glands and lymph nodes. In the adult brain, expressed CC in the superior frontal gyrus, putamen, caudate nucleus, cingulate CC gyrus, nucleus accumbens, hippocampus, pons and amygdala, as well as CC the hypothalamus and pituitary. Expression levels are higher in early CC (7-9 weeks) than term placentas. Expression levels were increased in CC both early placentas and molar pregnancies and were reduced in CC choriocarcinoma cells. Expressed at higher levels in first trimester CC trophoblasts than at term of gestation. Also found in the extravillous CC trophoblast suggesting endocrine/paracrine activation mechanism. CC {ECO:0000269|PubMed:11385580, ECO:0000269|PubMed:11387329, CC ECO:0000269|PubMed:11414709, ECO:0000269|PubMed:11457843, CC ECO:0000269|PubMed:12414911, ECO:0000269|PubMed:15020672}. CC -!- DISEASE: Hypogonadotropic hypogonadism 8 with or without anosmia (HH8) CC [MIM:614837]: A disorder characterized by absent or incomplete sexual CC maturation by the age of 18 years, in conjunction with low levels of CC circulating gonadotropins and testosterone and no other abnormalities CC of the hypothalamic-pituitary axis. In some cases, it is associated CC with non-reproductive phenotypes, such as anosmia, cleft palate, and CC sensorineural hearing loss. Anosmia or hyposmia is related to the CC absence or hypoplasia of the olfactory bulbs and tracts. Hypogonadism CC is due to deficiency in gonadotropin-releasing hormone and probably CC results from a failure of embryonic migration of gonadotropin-releasing CC hormone-synthesizing neurons. In the presence of anosmia, idiopathic CC hypogonadotropic hypogonadism is referred to as Kallmann syndrome, CC whereas in the presence of a normal sense of smell, it has been termed CC normosmic idiopathic hypogonadotropic hypogonadism (nIHH). HH8 CC inheritance pattern is autosomal recessive. CC {ECO:0000269|PubMed:12944565, ECO:0000269|PubMed:14573733, CC ECO:0000269|PubMed:15598687, ECO:0000269|PubMed:17164310, CC ECO:0000269|PubMed:18772143, ECO:0000269|PubMed:23643382, CC ECO:0000269|PubMed:25077900, ECO:0000269|PubMed:25147978}. Note=The CC disease is caused by variants affecting distinct genetic loci, CC including the gene represented in this entry. The genetics of CC hypogonadotropic hypogonadism involves various modes of transmission. CC Oligogenic inheritance has been reported in some patients carrying CC mutations in KISS1R as well as in other HH-associated genes including CC FGFR1 and IL17RD (PubMed:23643382). {ECO:0000269|PubMed:23643382}. CC -!- DISEASE: Precocious puberty, central 1 (CPPB1) [MIM:176400]: A CC condition defined as the development of secondary sexual CC characteristics in boys and girls at a chronological age that is 2.5 CC standard deviations below the mean age at onset of puberty in the CC population. Central precocious puberty results from premature CC activation of the hypothalamic-pituitary-gonadal axis. CC {ECO:0000269|PubMed:18272894}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- SIMILARITY: Belongs to the G protein-coupled receptor 1 family. CC {ECO:0000255|PROSITE-ProRule:PRU00521}. CC -!- WEB RESOURCE: Name=Protein Spotlight; Note=Tintin's blight - Issue 58 CC of May 2005; CC URL="https://www.proteinspotlight.org/back_issues/058"; 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; AB051065; BAB55446.1; -; mRNA. DR EMBL; AF343725; AAK83235.1; -; mRNA. DR EMBL; AJ309020; CAC40817.1; -; mRNA. DR EMBL; AY029541; AAK33126.1; -; mRNA. DR EMBL; AY253981; AAP82929.1; -; mRNA. DR EMBL; AY253982; AAP82930.1; -; mRNA. DR EMBL; EU883577; ACG60651.1; -; mRNA. DR EMBL; AC005379; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471139; EAW69583.1; -; Genomic_DNA. DR EMBL; BC140825; AAI40826.1; -; mRNA. DR EMBL; BC141812; AAI41813.1; -; mRNA. DR CCDS; CCDS12049.1; -. DR RefSeq; NP_115940.2; NM_032551.5. DR PDB; 7YQE; X-ray; 3.50 A; A/B=333-357. DR PDB; 8XGO; EM; 2.68 A; A=1-398. DR PDB; 8XGS; EM; 2.95 A; A=1-398. DR PDB; 8XGU; EM; 3.00 A; A=1-398. DR PDB; 8ZJD; EM; 3.06 A; R=2-355. DR PDB; 8ZJE; EM; 3.07 A; R=1-398. DR AlphaFoldDB; Q969F8; -. DR EMDB; EMD-38329; -. DR EMDB; EMD-38331; -. DR EMDB; EMD-38332; -. DR EMDB; EMD-60141; -. DR EMDB; EMD-60142; -. DR SMR; Q969F8; -. DR BioGRID; 124162; 4. DR CORUM; Q969F8; -. DR FunCoup; Q969F8; 620. DR IntAct; Q969F8; 23. DR MINT; Q969F8; -. DR NDEx; IQUERY-CP-KISS1R; 2 NDEx IQuery Curated Pathways. DR STRING; 9606.ENSP00000234371; -. DR BindingDB; Q969F8; -. DR ChEMBL; CHEMBL5413; -. DR DrugBank; DB05967; ANZ-100. DR DrugBank; DB16210; Kisspeptin-10. DR DrugCentral; Q969F8; -. DR GuidetoPHARMACOLOGY; 266; -. DR TCDB; 9.A.14.13.14; the g-protein-coupled receptor (gpcr) family. DR GlyCosmos; Q969F8; 3 sites, No reported glycans. DR GlyGen; Q969F8; 3 sites. DR iPTMnet; Q969F8; -. DR PhosphoSitePlus; Q969F8; -. DR BioMuta; KISS1R; -. DR DMDM; 125987836; -. DR MassIVE; Q969F8; -. DR PaxDb; 9606-ENSP00000234371; -. DR PeptideAtlas; Q969F8; -. DR ProteomicsDB; 75750; -. DR Antibodypedia; 10260; 334 antibodies from 35 providers. DR DNASU; 84634; -. DR Ensembl; ENST00000234371.10; ENSP00000234371.3; ENSG00000116014.11. DR GeneID; 84634; -. DR KEGG; hsa:84634; -. DR MANE-Select; ENST00000234371.10; ENSP00000234371.3; NM_032551.5; NP_115940.2. DR UCSC; uc002lqk.4; human. DR AGR; HGNC:4510; -. DR ClinPGx; PA28899; -. DR CTD; 84634; -. DR DisGeNET; 84634; -. DR GeneCards; KISS1R; -. DR GeneReviews; KISS1R; -. DR HGNC; HGNC:4510; KISS1R. DR HPA; ENSG00000116014; Group enriched (brain, pancreas, pituitary gland). DR MalaCards; KISS1R; -. DR MIM; 176400; phenotype. DR MIM; 604161; gene. DR MIM; 614837; phenotype. DR OpenTargets; ENSG00000116014; -. DR Orphanet; 650077; Genetic central precocious puberty in female. DR Orphanet; 650097; Genetic central precocious puberty in male. DR Orphanet; 432; Normosmic congenital hypogonadotropic hypogonadism. DR VEuPathDB; HostDB:ENSG00000116014; -. DR eggNOG; KOG3656; Eukaryota. DR GeneTree; ENSGT00940000157017; -. DR HOGENOM; CLU_009579_6_4_1; -. DR InParanoid; Q969F8; -. DR OMA; LYQMGHP; -. DR OrthoDB; 2132067at2759; -. DR PAN-GO; Q969F8; 4 GO annotations based on evolutionary models. DR PhylomeDB; Q969F8; -. DR PathwayCommons; Q969F8; -. DR Reactome; R-HSA-375276; Peptide ligand-binding receptors. DR Reactome; R-HSA-416476; G alpha (q) signalling events. DR SignaLink; Q969F8; -. DR SIGNOR; Q969F8; -. DR Agora; ENSG00000116014; -. DR BioGRID-ORCS; 84634; 17 hits in 1148 CRISPR screens. DR GeneWiki; KiSS1-derived_peptide_receptor; -. DR GenomeRNAi; 84634; -. DR Pharos; Q969F8; Tchem. DR PRO; PR:Q969F8; -. DR Proteomes; UP000005640; Chromosome 19. DR RNAct; Q969F8; protein. DR Bgee; ENSG00000116014; Expressed in pons and 93 other cell types or tissues. DR ExpressionAtlas; Q969F8; baseline and differential. DR GO; GO:0009986; C:cell surface; IEA:Ensembl. DR GO; GO:0005929; C:cilium; IDA:MGI. DR GO; GO:0016020; C:membrane; IDA:UniProtKB. DR GO; GO:0005886; C:plasma membrane; IDA:HPA. DR GO; GO:0004930; F:G protein-coupled receptor activity; IDA:UniProt. DR GO; GO:0060090; F:molecular adaptor activity; IEA:Ensembl. DR GO; GO:0008188; F:neuropeptide receptor activity; IDA:UniProtKB. DR GO; GO:0007186; P:G protein-coupled receptor signaling pathway; NAS:UniProtKB. DR GO; GO:0045779; P:negative regulation of bone resorption; ISS:UniProtKB. DR GO; GO:0045671; P:negative regulation of osteoclast differentiation; ISS:UniProt. DR GO; GO:0007218; P:neuropeptide signaling pathway; IBA:GO_Central. DR GO; GO:0007200; P:phospholipase C-activating G protein-coupled receptor signaling pathway; IDA:UniProt. DR GO; GO:0032278; P:positive regulation of gonadotropin secretion; IMP:UniProt. DR GO; GO:0046887; P:positive regulation of hormone secretion; IBA:GO_Central. DR GO; GO:1904181; P:positive regulation of membrane depolarization; TAS:UniProt. DR GO; GO:1904062; P:regulation of monoatomic cation transmembrane transport; IEA:Ensembl. DR CDD; cd15095; 7tmA_KiSS1R; 1. DR FunFam; 1.20.1070.10:FF:000171; KISS1 receptor b; 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; IPR008103; KiSS_1_rcpt. DR PANTHER; PTHR45695:SF23; GALANIN-LIKE G-PROTEIN COUPLED RECEPTOR NPR-9; 1. DR PANTHER; PTHR45695; LEUCOKININ RECEPTOR-RELATED; 1. DR Pfam; PF00001; 7tm_1; 1. DR PRINTS; PR00237; GPCRRHODOPSN. DR PRINTS; PR01728; KISS1RECEPTR. DR SUPFAM; SSF81321; Family A G protein-coupled receptor-like; 1. DR PROSITE; PS50262; G_PROTEIN_RECEP_F1_2; 1. DR PDBsum; 7YQE; -. DR PDBsum; 8XGO; -. DR PDBsum; 8XGS; -. DR PDBsum; 8XGU; -. DR PDBsum; 8ZJD; -. DR PDBsum; 8ZJE; -. PE 1: Evidence at protein level; KW 3D-structure; Cell membrane; Disease variant; Disulfide bond; KW G protein-coupled receptor; Glycoprotein; Hypogonadotropic hypogonadism; KW Membrane; Proteomics identification; Receptor; Reference proteome; KW Transducer; Transmembrane; Transmembrane helix. FT CHAIN 1..398 FT /note="KiSS-1 receptor" FT /id="PRO_0000069695" FT TOPO_DOM 1..46 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 47..67 FT /note="Helical; Name=1" FT /evidence="ECO:0000255" FT TOPO_DOM 68..78 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 79..101 FT /note="Helical; Name=2" FT /evidence="ECO:0000255" FT TOPO_DOM 102..120 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 121..138 FT /note="Helical; Name=3" FT /evidence="ECO:0000255" FT TOPO_DOM 139..157 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 158..178 FT /note="Helical; Name=4" FT /evidence="ECO:0000255" FT TOPO_DOM 179..202 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 203..223 FT /note="Helical; Name=5" FT /evidence="ECO:0000255" FT TOPO_DOM 224..263 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 264..284 FT /note="Helical; Name=6" FT /evidence="ECO:0000255" FT TOPO_DOM 285..305 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 306..328 FT /note="Helical; Name=7" FT /evidence="ECO:0000255" FT TOPO_DOM 329..398 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT REGION 341..363 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT CARBOHYD 10 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 18 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 28 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT DISULFID 115..191 FT /evidence="ECO:0000269|PubMed:38935498, FT ECO:0000269|PubMed:39151001, ECO:0007744|PDB:8XGO, FT ECO:0007744|PDB:8XGS, ECO:0007744|PDB:8XGU, FT ECO:0007744|PDB:8ZJD" FT VARIANT 102 FT /note="L -> P (in HH8; absence of inositol phosphate FT accumulation under kisspeptin challenge; normal affinity FT for kisspeptin; dbSNP:rs104894703)" FT /evidence="ECO:0000269|PubMed:17164310" FT /id="VAR_043906" FT VARIANT 148 FT /note="L -> S (in HH8; likely pathogenic; decreased G FT protein-coupled peptide receptor activity; severely FT decreased phospholipase C-activating G protein-coupled FT receptor signaling pathway; decreased ERK1/ERK2 FT phosphorylation; does not affect localization to cell FT membrane; does not affect kisspeptin-10 binding; inhibits FT catalytic activation of G(q); dbSNP:rs28939719)" FT /evidence="ECO:0000269|PubMed:14573733, FT ECO:0000269|PubMed:18772143, ECO:0000269|PubMed:25147978" FT /id="VAR_021392" FT VARIANT 189 FT /note="A -> T (in HH8; benign; the patient also carries a FT mutation in FGFR1; phenotype consistent with normosmic FT idiopathic hypogonadotropic hypogonadism; FT dbSNP:rs73507527)" FT /evidence="ECO:0000269|PubMed:23643382" FT /id="VAR_069961" FT VARIANT 194 FT /note="A -> D (in HH8; phenotype consistent with Kallmann FT syndrome; the patient also carries a mutation in IL17RD; FT dbSNP:rs397514699)" FT /evidence="ECO:0000269|PubMed:23643382" FT /id="VAR_069962" FT VARIANT 223 FT /note="C -> R (in HH8; exhibit profoundly impaired FT signaling; dbSNP:rs2037102475)" FT /evidence="ECO:0000269|PubMed:15598687" FT /id="VAR_021393" FT VARIANT 262 FT /note="S -> L (in HH8; dbSNP:rs745580229)" FT /evidence="ECO:0000269|PubMed:25077900" FT /id="VAR_072975" FT VARIANT 297 FT /note="R -> L (in HH8; mild reduction in ligand-stimulated FT activity across the ligand dose range; dbSNP:rs144670595)" FT /evidence="ECO:0000269|PubMed:15598687" FT /id="VAR_021394" FT VARIANT 364 FT /note="L -> H (in dbSNP:rs350132)" FT /evidence="ECO:0000269|PubMed:11385580, FT ECO:0000269|PubMed:11414709, ECO:0000269|PubMed:11457843, FT ECO:0000269|PubMed:14573733, ECO:0000269|PubMed:15489334, FT ECO:0000269|PubMed:15598687, ECO:0000269|Ref.8" FT /id="VAR_021395" FT VARIANT 386 FT /note="R -> P (in CPPB1; reduced rate of decline in FT inositol phosphate accumulation after kisspeptin FT stimulation; prolonged phosphorylation of ERK; FT dbSNP:rs121908499)" FT /evidence="ECO:0000269|PubMed:18272894" FT /id="VAR_043907" FT MUTAGEN 99 FT /note="T->A: Decreased sensitivity to activation by FT kisspeptin-54 and reduced phospholipase C-activating G FT protein-coupled receptor signaling." FT /evidence="ECO:0000269|PubMed:39151001" FT MUTAGEN 119 FT /note="N->A: Decreased sensitivity to activation by FT kisspeptin-54 and reduced phospholipase C-activating G FT protein-coupled receptor signaling." FT /evidence="ECO:0000269|PubMed:39151001" FT MUTAGEN 122 FT /note="Q->A: Decreased sensitivity to activation by FT kisspeptin-54 and reduced phospholipase C-activating G FT protein-coupled receptor signaling." FT /evidence="ECO:0000269|PubMed:39151001" FT MUTAGEN 123 FT /note="Q->A: Decreased sensitivity to activation by FT kisspeptin-54 and reduced phospholipase C-activating G FT protein-coupled receptor signaling." FT /evidence="ECO:0000269|PubMed:39151001" FT MUTAGEN 148 FT /note="L->A,F,T: Mildly decreased phospholipase FT C-activating G protein-coupled receptor signaling in FT response to kisspeptin-10." FT /evidence="ECO:0000269|PubMed:18772143" FT MUTAGEN 148 FT /note="L->E,R: Severely decreased phospholipase FT C-activating G protein-coupled receptor signaling in FT response to kisspeptin-10." FT /evidence="ECO:0000269|PubMed:18772143" FT MUTAGEN 181 FT /note="H->A: Decreased sensitivity to activation by FT kisspeptin-54 and reduced phospholipase C-activating G FT protein-coupled receptor signaling." FT /evidence="ECO:0000269|PubMed:39151001" FT MUTAGEN 193 FT /note="E->A: Loss of sensitivity to activation by FT kisspeptin-54 and loss of phospholipase C-activating G FT protein-coupled receptor signaling." FT /evidence="ECO:0000269|PubMed:39151001" FT MUTAGEN 297 FT /note="R->A: Decreased sensitivity to activation by FT kisspeptin-54 and reduced phospholipase C-activating G FT protein-coupled receptor signaling." FT /evidence="ECO:0000269|PubMed:39151001" FT MUTAGEN 302 FT /note="Y->A: Decreased sensitivity to activation by FT kisspeptin-54 and reduced phospholipase C-activating G FT protein-coupled receptor signaling." FT /evidence="ECO:0000269|PubMed:39151001" FT MUTAGEN 305 FT /note="K->A: Decreased sensitivity to activation by FT kisspeptin-54 and reduced phospholipase C-activating G FT protein-coupled receptor signaling." FT /evidence="ECO:0000269|PubMed:39151001" FT MUTAGEN 309 FT /note="H->A: Decreased sensitivity to activation by FT kisspeptin-54 and reduced phospholipase C-activating G FT protein-coupled receptor signaling." FT /evidence="ECO:0000269|PubMed:39151001" FT MUTAGEN 313 FT /note="Y->A: Decreased sensitivity to activation by FT kisspeptin-54 and reduced phospholipase C-activating G FT protein-coupled receptor signaling." FT /evidence="ECO:0000269|PubMed:39151001" FT MUTAGEN 336 FT /note="R->A: Decreased interaction with SRC; when FT associated in cis with A-339. Decreased interaction with FT DUSP18; when associated in cis with A-339." FT /evidence="ECO:0000269|PubMed:38346942" FT MUTAGEN 339 FT /note="P->A: Decreased interaction with SRC; when FT associated in cis with A-336. Decreased interaction with FT DUSP18; when associated in cis with A-336." FT /evidence="ECO:0000269|PubMed:38346942" FT HELIX 40..44 FT /evidence="ECO:0007829|PDB:8XGO" FT HELIX 46..69 FT /evidence="ECO:0007829|PDB:8XGO" FT HELIX 71..73 FT /evidence="ECO:0007829|PDB:8XGO" FT HELIX 76..101 FT /evidence="ECO:0007829|PDB:8XGO" FT TURN 102..104 FT /evidence="ECO:0007829|PDB:8XGO" FT STRAND 105..107 FT /evidence="ECO:0007829|PDB:8XGO" FT HELIX 112..145 FT /evidence="ECO:0007829|PDB:8XGO" FT HELIX 149..152 FT /evidence="ECO:0007829|PDB:8XGO" FT HELIX 156..174 FT /evidence="ECO:0007829|PDB:8XGO" FT HELIX 175..180 FT /evidence="ECO:0007829|PDB:8XGO" FT STRAND 181..184 FT /evidence="ECO:0007829|PDB:8XGO" FT STRAND 186..188 FT /evidence="ECO:0007829|PDB:8XGO" FT STRAND 190..193 FT /evidence="ECO:0007829|PDB:8XGO" FT HELIX 198..209 FT /evidence="ECO:0007829|PDB:8XGO" FT HELIX 210..214 FT /evidence="ECO:0007829|PDB:8XGO" FT HELIX 215..235 FT /evidence="ECO:0007829|PDB:8XGO" FT STRAND 242..245 FT /evidence="ECO:0007829|PDB:8XGO" FT HELIX 246..287 FT /evidence="ECO:0007829|PDB:8XGO" FT STRAND 292..294 FT /evidence="ECO:0007829|PDB:8XGO" FT STRAND 296..298 FT /evidence="ECO:0007829|PDB:8XGU" FT HELIX 299..320 FT /evidence="ECO:0007829|PDB:8XGO" FT HELIX 321..325 FT /evidence="ECO:0007829|PDB:8XGO" FT HELIX 328..335 FT /evidence="ECO:0007829|PDB:8XGO" FT HELIX 337..343 FT /evidence="ECO:0007829|PDB:7YQE" SQ SEQUENCE 398 AA; 42586 MW; ECAE2208848F5B06 CRC64; MHTVATSGPN ASWGAPANAS GCPGCGANAS DGPVPSPRAV DAWLVPLFFA ALMLLGLVGN SLVIYVICRH KPMRTVTNFY IANLAATDVT FLLCCVPFTA LLYPLPGWVL GDFMCKFVNY IQQVSVQATC ATLTAMSVDR WYVTVFPLRA LHRRTPRLAL AVSLSIWVGS AAVSAPVLAL HRLSPGPRAY CSEAFPSRAL ERAFALYNLL ALYLLPLLAT CACYAAMLRH LGRVAVRPAP ADSALQGQVL AERAGAVRAK VSRLVAAVVL LFAACWGPIQ LFLVLQALGP AGSWHPRSYA AYALKTWAHC MSYSNSALNP LLYAFLGSHF RQAFRRVCPC APRRPRRPRR PGPSDPAAPH AELLRLGSHP APARAQKPGS SGLAARGLCV LGEDNAPL //