KiSS1-derived peptide receptor explained

The KiSS1-derived peptide receptor (also known as GPR54 or the Kisspeptin receptor) is a G protein-coupled receptor^[1] which binds the peptide hormone kisspeptin (metastin).^{[2] [3] [4]} Kisspeptin is encoded by the metastasis suppressor gene KISS1, which is expressed in a variety of endocrine and gonadal tissues.^[5] Activation of the kisspeptin receptor is linked to the phospholipase C and inositol trisphosphate second messenger cascades inside the cell.^[6]

Kisspeptins are neuropeptides synthesized in the hypothalamus and encoded by the KISS1 gene. The KISS1 gene encodes the G protein-coupled receptor 54 (known as KISS1R or GPR54) and plays a crucial role in regulating reproduction, pubertal maturation, and metabolic function.^{[7] [8] [9]} KISS1 neurons located in the arcuate nucleus (ARC) of the mediobasal hypothalamus (MBH) project to GnRH neurons in the median eminence, which expresses KISS1R, to stimulate LH secretions in a pulsatile manner from the anterior pituitary to initiate ovulation/ pubertal maturation.^{[10] [11] [12]} The KISS1 and KISS1R/GPR54 genes have been detected in the brain, pituitary, placenta, pancreas, liver, and small intestine.

Function

Kisspeptin is involved in the regulation of endocrine function and the onset of puberty, with activation of the kisspeptin receptor triggering release of gonadotropin-releasing hormone (GnRH),^{[13] [14]} and release of kisspeptin itself being inhibited by oestradiol but enhanced by GnRH.^[15] Reductions in kisspeptin levels with age may conversely be one of the reasons behind age-related declines in levels of other endocrine hormones such as luteinizing hormone.^[16]

Clinical significance

Alterations in the KISS1/KISS1R signaling pathway have been linked to multiple physiological conditions, including metabolic and reproductive abnormalities.^[17] A knockout model of GPR54/KISS1R in mice showed hypogonadism, and the mice failed to reach puberty. The KISS1 gene has been stated to suppress the metastasis of malignant melanomas.^[18] KISS1R signaling pathway has been characterized in the suppression of tumors and has anti-metastatic effects in several cancers, including breast cancer.^{[19] [20]}

Activation of KISS1R elicits a neuroendocrine response leading to pubertal maturation. This is indicated by intermittent kisspeptin-10 administration to pre-pubertal animals resulting in activation of the hypothalamic-pituitary axis and subsequent precocious puberty in rats and primates.^{[21] [22]} Mutations in the kisspeptin receptor KISS1R have resulted in isolated hypogonadotropic hypogonadism (IHH), characterized by delayed or absence of puberty ^[23]

Ligands

No non-peptide ligands for this receptor have yet been discovered, but as of 2009 both selective agonist and antagonist peptides are known.

Agonists

• Kisspeptin (kisspeptin-54, metastin)
• Kisspeptin-10 (112-121 C-terminal fragment)^[24]
• KISS1-305
• MVT-602 (RVT-602, TAK-448)
• TAK-683

Antagonists

• Kisspeptin-10 analogues modified with amino substitutions^[25]
• Kisspeptin-234

Further reading

• Colledge WH . GPR54 and puberty . Trends in Endocrinology and Metabolism . 15 . 9 . 448–453 . November 2004 . 15519892 . 10.1016/j.tem.2004.09.008 . 44517221 .
• Kaiser UB, Kuohung W . KiSS-1 and GPR54 as new players in gonadotropin regulation and puberty . Endocrine . 26 . 3 . 277–284 . April 2005 . 16034182 . 10.1385/ENDO:26:3:277 . 22795399 .
• Seminara SB . Metastin and its G protein-coupled receptor, GPR54: critical pathway modulating GnRH secretion . Frontiers in Neuroendocrinology . 26 . 3–4 . 131–138 . 2006 . 16309735 . 10.1016/j.yfrne.2005.10.001 . 40864875 .
• Tena-Sempere M . GPR54 and kisspeptin in reproduction . Human Reproduction Update . 12 . 5 . 631–639 . 2006 . 16731583 . 10.1093/humupd/dml023 . free .
• Cerrato F, Seminara SB . Human genetics of GPR54 . Reviews in Endocrine & Metabolic Disorders . 8 . 1 . 47–55 . March 2007 . 17334928 . 10.1007/s11154-007-9027-3 . 13041509 .
• Lee DK, Nguyen T, O'Neill GP, Cheng R, Liu Y, Howard AD, Coulombe N, Tan CP, Tang-Nguyen AT, George SR, O'Dowd BF . 6 . Discovery of a receptor related to the galanin receptors . FEBS Letters . 446 . 1 . 103–107 . March 1999 . 10100623 . 10.1016/S0014-5793(99)00009-5 . 38910830 .
• Ohtaki T, Shintani Y, Honda S, Matsumoto H, Hori A, Kanehashi K, Terao Y, Kumano S, Takatsu Y, Masuda Y, Ishibashi Y, Watanabe T, Asada M, Yamada T, Suenaga M, Kitada C, Usuki S, Kurokawa T, Onda H, Nishimura O, Fujino M . 6 . Metastasis suppressor gene KiSS-1 encodes peptide ligand of a G-protein-coupled receptor . Nature . 411 . 6837 . 613–617 . May 2001 . 11385580 . 10.1038/35079135 . 205017670 . 2001Natur.411..613O .
• Muir AI, Chamberlain L, Elshourbagy NA, Michalovich D, Moore DJ, Calamari A, Szekeres PG, Sarau HM, Chambers JK, Murdock P, Steplewski K, Shabon U, Miller JE, Middleton SE, Darker JG, Larminie CG, Wilson S, Bergsma DJ, Emson P, Faull R, Philpott KL, Harrison DC . 6 . AXOR12, a novel human G protein-coupled receptor, activated by the peptide KiSS-1 . The Journal of Biological Chemistry . 276 . 31 . 28969–28975 . August 2001 . 11387329 . 10.1074/jbc.M102743200 . free.
• Clements MK, McDonald TP, Wang R, Xie G, O'Dowd BF, George SR, Austin CP, Liu Q . 6 . FMRFamide-related neuropeptides are agonists of the orphan G-protein-coupled receptor GPR54 . Biochemical and Biophysical Research Communications . 284 . 5 . 1189–1193 . June 2001 . 11414709 . 10.1006/bbrc.2001.5098 .
• Kotani M, Detheux M, Vandenbogaerde A, Communi D, Vanderwinden JM, Le Poul E, Brézillon S, Tyldesley R, Suarez-Huerta N, Vandeput F, Blanpain C, Schiffmann SN, Vassart G, Parmentier M . 6 . The metastasis suppressor gene KiSS-1 encodes kisspeptins, the natural ligands of the orphan G protein-coupled receptor GPR54 . The Journal of Biological Chemistry . 276 . 37 . 34631–34636 . September 2001 . 11457843 . 10.1074/jbc.M104847200 . free .
• Hori A, Honda S, Asada M, Ohtaki T, Oda K, Watanabe T, Shintani Y, Yamada T, Suenaga M, Kitada C, Onda H, Kurokawa T, Nishimura O, Fujino M . 6 . Metastin suppresses the motility and growth of CHO cells transfected with its receptor . Biochemical and Biophysical Research Communications . 286 . 5 . 958–963 . September 2001 . 11527393 . 10.1006/bbrc.2001.5470 .
• Ringel MD, Hardy E, Bernet VJ, Burch HB, Schuppert F, Burman KD, Saji M . Metastin receptor is overexpressed in papillary thyroid cancer and activates MAP kinase in thyroid cancer cells . The Journal of Clinical Endocrinology and Metabolism . 87 . 5 . 2399 . May 2002 . 11994395 . 10.1210/jcem.87.5.8626 . free .
• Janneau JL, Maldonado-Estrada J, Tachdjian G, Miran I, Motté N, Saulnier P, Sabourin JC, Coté JF, Simon B, Frydman R, Chaouat G, Bellet D . 6 . Transcriptional expression of genes involved in cell invasion and migration by normal and tumoral trophoblast cells . The Journal of Clinical Endocrinology and Metabolism . 87 . 11 . 5336–5339 . November 2002 . 12414911 . 10.1210/jc.2002-021093 . free .
• Bo-Abbas Y, Acierno JS, Shagoury JK, Crowley WF, Seminara SB . Autosomal recessive idiopathic hypogonadotropic hypogonadism: genetic analysis excludes mutations in the gonadotropin-releasing hormone (GnRH) and GnRH receptor genes . The Journal of Clinical Endocrinology and Metabolism . 88 . 6 . 2730–2737 . June 2003 . 12788881 . 10.1210/jc.2002-021948 . free .
• Ikeguchi M, Hirooka Y, Kaibara N . Quantitative reverse transcriptase polymerase chain reaction analysis for KiSS-1 and orphan G-protein-coupled receptor (hOT7T175) gene expression in hepatocellular carcinoma . Journal of Cancer Research and Clinical Oncology . 129 . 9 . 531–535 . September 2003 . 12898236 . 10.1007/s00432-003-0469-z . 20323621 .
• de Roux N, Genin E, Carel JC, Matsuda F, Chaussain JL, Milgrom E . Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54 . Proceedings of the National Academy of Sciences of the United States of America . 100 . 19 . 10972–10976 . September 2003 . 12944565 . 196911 . 10.1073/pnas.1834399100 . free . 2003PNAS..10010972D .
• Seminara SB, Messager S, Chatzidaki EE, Thresher RR, Acierno JS, Shagoury JK, Bo-Abbas Y, Kuohung W, Schwinof KM, Hendrick AG, Zahn D, Dixon J, Kaiser UB, Slaugenhaupt SA, Gusella JF, O'Rahilly S, Carlton MB, Crowley WF, Aparicio SA, Colledge WH . 6 . The GPR54 gene as a regulator of puberty . The New England Journal of Medicine . 349 . 17 . 1614–1627 . October 2003 . 14573733 . 10.1056/NEJMoa035322 . free .
• Ikeguchi M, Yamaguchi K, Kaibara N . Clinical significance of the loss of KiSS-1 and orphan G-protein-coupled receptor (hOT7T175) gene expression in esophageal squamous cell carcinoma . Clinical Cancer Research . 10 . 4 . 1379–1383 . February 2004 . 14977840 . 10.1158/1078-0432.CCR-1519-02 . free .
• Bilban M, Ghaffari-Tabrizi N, Hintermann E, Bauer S, Molzer S, Zoratti C, Malli R, Sharabi A, Hiden U, Graier W, Knöfler M, Andreae F, Wagner O, Quaranta V, Desoye G . 6 . Kisspeptin-10, a KiSS-1/metastin-derived decapeptide, is a physiological invasion inhibitor of primary human trophoblasts . Journal of Cell Science . 117 . Pt 8 . 1319–1328 . March 2004 . 15020672 . 10.1242/jcs.00971 . 38523546 .

External links

• Web site: KiSS1-Derived Peptide Receptors . IUPHAR Database of Receptors and Ion Channels . International Union of Basic and Clinical Pharmacology . 2007-11-02 . 2016-02-06 . https://web.archive.org/web/20160206094855/http://www.iuphar-db.org/GPCR/ChapterMenuForward?chapterID=1337 . dead .

Notes and References

1. Lee DK, Nguyen T, O'Neill GP, Cheng R, Liu Y, Howard AD, Coulombe N, Tan CP, Tang-Nguyen AT, George SR, O'Dowd BF . 6 . Discovery of a receptor related to the galanin receptors . FEBS Letters . 446 . 1 . 103–107 . March 1999 . 10100623 . 10.1016/S0014-5793(99)00009-5 . 38910830 .
2. Ohtaki T, Shintani Y, Honda S, Matsumoto H, Hori A, Kanehashi K, Terao Y, Kumano S, Takatsu Y, Masuda Y, Ishibashi Y, Watanabe T, Asada M, Yamada T, Suenaga M, Kitada C, Usuki S, Kurokawa T, Onda H, Nishimura O, Fujino M . 6 . Metastasis suppressor gene KiSS-1 encodes peptide ligand of a G-protein-coupled receptor . Nature . 411 . 6837 . 613–617 . May 2001 . 11385580 . 10.1038/35079135 . 205017670 . 2001Natur.411..613O .
3. Muir AI, Chamberlain L, Elshourbagy NA, Michalovich D, Moore DJ, Calamari A, Szekeres PG, Sarau HM, Chambers JK, Murdock P, Steplewski K, Shabon U, Miller JE, Middleton SE, Darker JG, Larminie CG, Wilson S, Bergsma DJ, Emson P, Faull R, Philpott KL, Harrison DC . 6 . AXOR12, a novel human G protein-coupled receptor, activated by the peptide KiSS-1 . The Journal of Biological Chemistry . 276 . 31 . 28969–28975 . August 2001 . 11387329 . 10.1074/jbc.M102743200 . free.
4. Kotani M, Detheux M, Vandenbogaerde A, Communi D, Vanderwinden JM, Le Poul E, Brézillon S, Tyldesley R, Suarez-Huerta N, Vandeput F, Blanpain C, Schiffmann SN, Vassart G, Parmentier M . 6 . The metastasis suppressor gene KiSS-1 encodes kisspeptins, the natural ligands of the orphan G protein-coupled receptor GPR54 . The Journal of Biological Chemistry . 276 . 37 . 34631–34636 . September 2001 . 11457843 . 10.1074/jbc.M104847200 . free .
5. Richard N, Corvaisier S, Camacho E, Kottler ML . KiSS-1 and GPR54 at the pituitary level: overview and recent insights . Peptides . 30 . 1 . 123–129 . January 2009 . 18948153 . 10.1016/j.peptides.2008.09.015 . 22875820 .
6. Liu X, Lee K, Herbison AE . Kisspeptin excites gonadotropin-releasing hormone neurons through a phospholipase C/calcium-dependent pathway regulating multiple ion channels . Endocrinology . 149 . 9 . 4605–4614 . September 2008 . 18483150 . 6116891 . 10.1210/en.2008-0321 .
7. Roseweir AK, Millar RP . The role of kisspeptin in the control of gonadotrophin secretion . Human Reproduction Update . 15 . 2 . 203–212 . 2008-11-05 . 19109311 . 10.1093/humupd/dmn058 . free .
8. Tolson KP, Garcia C, Yen S, Simonds S, Stefanidis A, Lawrence A, Smith JT, Kauffman AS . 6 . Impaired kisspeptin signaling decreases metabolism and promotes glucose intolerance and obesity . The Journal of Clinical Investigation . 124 . 7 . 3075–3079 . July 2014 . 24937427 . 10.1172/jci71075 . 4071390 .
9. Song WJ, Mondal P, Wolfe A, Alonso LC, Stamateris R, Ong BW, Lim OC, Yang KS, Radovick S, Novaira HJ, Farber EA, Farber CR, Turner SD, Hussain MA . 6 . Glucagon regulates hepatic kisspeptin to impair insulin secretion . Cell Metabolism . 19 . 4 . 667–681 . April 2014 . 24703698 . 10.1016/j.cmet.2014.03.005 . 4058888 .
10. Yeo SH, Colledge WH . The Role of Kiss1 Neurons As Integrators of Endocrine, Metabolic, and Environmental Factors in the Hypothalamic-Pituitary-Gonadal Axis . Frontiers in Endocrinology . 9 . 188 . 2018-04-26 . 29755406 . 10.3389/fendo.2018.00188 . 5932150 . free .
11. Navarro VM, Castellano JM, Fernández-Fernández R, Barreiro ML, Roa J, Sanchez-Criado JE, Aguilar E, Dieguez C, Pinilla L, Tena-Sempere M . 6 . Developmental and hormonally regulated messenger ribonucleic acid expression of KiSS-1 and its putative receptor, GPR54, in rat hypothalamus and potent luteinizing hormone-releasing activity of KiSS-1 peptide . Endocrinology . 145 . 10 . 4565–4574 . October 2004 . 15242985 . 10.1210/en.2004-0413 . 14817781 .
12. De Bond JP, Tolson KP, Nasamran C, Kauffman AS, Smith JT . Unaltered Hypothalamic Metabolic Gene Expression in Kiss1r Knockout Mice Despite Obesity and Reduced Energy Expenditure . Journal of Neuroendocrinology . 28 . 10 . October 2016 . 27601011 . 10.1111/jne.12430 . 5083214 . 3542864 .
13. Shahab M, Mastronardi C, Seminara SB, Crowley WF, Ojeda SR, Plant TM . Increased hypothalamic GPR54 signaling: a potential mechanism for initiation of puberty in primates . Proceedings of the National Academy of Sciences of the United States of America . 102 . 6 . 2129–2134 . February 2005 . 15684075 . 548549 . 10.1073/pnas.0409822102 . free . 2005PNAS..102.2129S .
14. Plant TM, Ramaswamy S, Dipietro MJ . Repetitive activation of hypothalamic G protein-coupled receptor 54 with intravenous pulses of kisspeptin in the juvenile monkey (Macaca mulatta) elicits a sustained train of gonadotropin-releasing hormone discharges . Endocrinology . 147 . 2 . 1007–1013 . February 2006 . 16282350 . 10.1210/en.2005-1261 .
15. Richard N, Galmiche G, Corvaisier S, Caraty A, Kottler ML . KiSS-1 and GPR54 genes are co-expressed in rat gonadotrophs and differentially regulated in vivo by oestradiol and gonadotrophin-releasing hormone . Journal of Neuroendocrinology . 20 . 3 . 381–393 . March 2008 . 18208554 . 10.1111/j.1365-2826.2008.01653.x . 205345039 .
16. Neal-Perry G, Lebesgue D, Lederman M, Shu J, Zeevalk GD, Etgen AM . The excitatory peptide kisspeptin restores the luteinizing hormone surge and modulates amino acid neurotransmission in the medial preoptic area of middle-aged rats . Endocrinology . 150 . 8 . 3699–3708 . August 2009 . 19423763 . 2717872 . 10.1210/en.2008-1667 .
17. Funes S, Hedrick JA, Vassileva G, Markowitz L, Abbondanzo S, Golovko A, Yang S, Monsma FJ, Gustafson EL . 6 . The KiSS-1 receptor GPR54 is essential for the development of the murine reproductive system . Biochemical and Biophysical Research Communications . 312 . 4 . 1357–1363 . December 2003 . 14652023 . 10.1016/j.bbrc.2003.11.066 .
18. Martins CM, Fernandes BF, Antecka E, Di Cesare S, Mansure JJ, Marshall JC, Burnier MN . Expression of the metastasis suppressor gene KISS1 in uveal melanoma . Eye . 22 . 5 . 707–711 . May 2008 . 18219339 . 10.1038/sj.eye.6703090 . free .
19. Cvetković D, Babwah AV, Bhattacharya M . Kisspeptin/KISS1R System in Breast Cancer . Journal of Cancer . 4 . 8 . 653–661 . September 2013 . 24155777 . 10.7150/jca.7626 . 3805993 .
20. Guzman S, Brackstone M, Wondisford F, Babwah AV, Bhattacharya M . KISS1/KISS1R and Breast Cancer: Metastasis Promoter . Seminars in Reproductive Medicine . 37 . 4 . 197–206 . July 2019 . 31972865 . 10.1055/s-0039-3400968 . 210883188 .
21. Navarro VM, Fernández-Fernández R, Castellano JM, Roa J, Mayen A, Barreiro ML, Gaytan F, Aguilar E, Pinilla L, Dieguez C, Tena-Sempere M . 6 . Advanced vaginal opening and precocious activation of the reproductive axis by KiSS-1 peptide, the endogenous ligand of GPR54 . The Journal of Physiology . 561 . Pt 2 . 379–386 . December 2004 . 15486019 . 10.1113/jphysiol.2004.072298 . 1665361 .
22. Plant TM, Ramaswamy S, Dipietro MJ . Repetitive activation of hypothalamic G protein-coupled receptor 54 with intravenous pulses of kisspeptin in the juvenile monkey (Macaca mulatta) elicits a sustained train of gonadotropin-releasing hormone discharges . Endocrinology . 147 . 2 . 1007–1013 . February 2006 . 16282350 . 10.1210/en.2005-1261 .
23. Silveira LG, Noel SD, Silveira-Neto AP, Abreu AP, Brito VN, Santos MG, Bianco SD, Kuohung W, Xu S, Gryngarten M, Escobar ME, Arnhold IJ, Mendonca BB, Kaiser UB, Latronico AC . 6 . Mutations of the KISS1 gene in disorders of puberty . The Journal of Clinical Endocrinology and Metabolism . 95 . 5 . 2276–2280 . May 2010 . 20237166 . 10.1210/jc.2009-2421 . 2869552 .
24. Mikkelsen JD, Bentsen AH, Ansel L, Simonneaux V, Juul A . Comparison of the effects of peripherally administered kisspeptins . Regulatory Peptides . 152 . 1–3 . 95–100 . January 2009 . 18940206 . 10.1016/j.regpep.2008.10.001 . 6587724 .
25. Roseweir AK, Kauffman AS, Smith JT, Guerriero KA, Morgan K, Pielecka-Fortuna J, Pineda R, Gottsch ML, Tena-Sempere M, Moenter SM, Terasawa E, Clarke IJ, Steiner RA, Millar RP . 6 . Discovery of potent kisspeptin antagonists delineate physiological mechanisms of gonadotropin regulation . The Journal of Neuroscience . 29 . 12 . 3920–3929 . March 2009 . 19321788 . 3035813 . 10.1523/JNEUROSCI.5740-08.2009 .