KiSS1-derived peptide receptor

The KiSS1-derived peptide receptor (also known as GPR54 or the Kisspeptin receptor) is a G protein-coupled receptor[5] which binds the peptide hormone kisspeptin (metastin).[6][7][8] Kisspeptin is encoded by the metastasis suppressor gene KISS1, which is expressed in a variety of endocrine and gonadal tissues.[9] Activation of the kisspeptin receptor is linked to the phospholipase C and inositol trisphosphate second messenger cascades inside the cell.[10]

KISS1R
Identifiers
AliasesKISS1R, AXOR12, CPPB1, GPR54, HH8, HOT7T175, KISS-1R, KiSS1-derived peptide receptor, KISS1 receptor
External IDsOMIM: 604161 MGI: 2148793 HomoloGene: 11411 GeneCards: KISS1R
Orthologs
SpeciesHumanMouse
Entrez

84634

114229

Ensembl

ENSG00000116014

ENSMUSG00000035773

UniProt

Q969F8

Q91V45

RefSeq (mRNA)

NM_032551

NM_053244
NM_001359010

RefSeq (protein)

NP_115940

NP_444474
NP_001345939

Location (UCSC)Chr 19: 0.92 – 0.92 MbChr 10: 79.75 – 79.76 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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.[11][12][13] 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.[14][15][16] The KISS1 and KISS1R/GPR54 genes have been detected in the brain, pituitary, placenta, pancreas, liver, and small intestine.[14]

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),[17][18] and release of kisspeptin itself being inhibited by oestradiol but enhanced by GnRH.[19] 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.[20]

Clinical significance

Alterations in the KISS1/KISS1R signaling pathway have been linked to multiple physiological conditions, including metabolic and reproductive abnormalities.[21] A knockout model of GPR54/KISS1R in mice showed hypogonadism, and the mice failed to reach puberty.[21] The KISS1 gene has been stated to suppress the metastasis of malignant melanomas.[22] KISS1R signaling pathway has been characterized in the suppression of tumors and has anti-metastatic effects in several cancers, including breast cancer.[23][24]

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.[25][26] Mutations in the kisspeptin receptor KISS1R have resulted in isolated hypogonadotropic hypogonadism (IHH), characterized by delayed or absence of puberty [27]

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)[28]
  • KISS1-305
  • MVT-602 (RVT-602, TAK-448)
  • TAK-683

Antagonists
  • Kisspeptin-10 analogues modified with amino substitutions[29]
  • Kisspeptin-234

References
  1. GRCh38: Ensembl release 89: ENSG00000116014 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000035773 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. Lee DK, Nguyen T, O'Neill GP, Cheng R, Liu Y, Howard AD, et al. (March 1999). "Discovery of a receptor related to the galanin receptors". FEBS Letters. 446 (1): 103–107. doi:10.1016/S0014-5793(99)00009-5. PMID 10100623. S2CID 38910830.
  6. Ohtaki T, Shintani Y, Honda S, Matsumoto H, Hori A, Kanehashi K, et al. (May 2001). "Metastasis suppressor gene KiSS-1 encodes peptide ligand of a G-protein-coupled receptor". Nature. 411 (6837): 613–617. Bibcode:2001Natur.411..613O. doi:10.1038/35079135. PMID 11385580. S2CID 205017670.
  7. Muir AI, Chamberlain L, Elshourbagy NA, Michalovich D, Moore DJ, Calamari A, et al. (August 2001). "AXOR12, a novel human G protein-coupled receptor, activated by the peptide KiSS-1". The Journal of Biological Chemistry. 276 (31): 28969–28975. doi:10.1074/jbc.M102743200. PMID 11387329.
  8. Kotani M, Detheux M, Vandenbogaerde A, Communi D, Vanderwinden JM, Le Poul E, et al. (September 2001). "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. doi:10.1074/jbc.M104847200. PMID 11457843.
  9. Richard N, Corvaisier S, Camacho E, Kottler ML (January 2009). "KiSS-1 and GPR54 at the pituitary level: overview and recent insights". Peptides. 30 (1): 123–129. doi:10.1016/j.peptides.2008.09.015. PMID 18948153. S2CID 22875820.
  10. Liu X, Lee K, Herbison AE (September 2008). "Kisspeptin excites gonadotropin-releasing hormone neurons through a phospholipase C/calcium-dependent pathway regulating multiple ion channels". Endocrinology. 149 (9): 4605–4614. doi:10.1210/en.2008-0321. PMC 6116891. PMID 18483150.
  11. Roseweir AK, Millar RP (2008-11-05). "The role of kisspeptin in the control of gonadotrophin secretion". Human Reproduction Update. 15 (2): 203–212. doi:10.1093/humupd/dmn058. PMID 19109311.
  12. Tolson KP, Garcia C, Yen S, Simonds S, Stefanidis A, Lawrence A, et al. (July 2014). "Impaired kisspeptin signaling decreases metabolism and promotes glucose intolerance and obesity". The Journal of Clinical Investigation. 124 (7): 3075–3079. doi:10.1172/jci71075. PMC 4071390. PMID 24937427.
  13. Song WJ, Mondal P, Wolfe A, Alonso LC, Stamateris R, Ong BW, et al. (April 2014). "Glucagon regulates hepatic kisspeptin to impair insulin secretion". Cell Metabolism. 19 (4): 667–681. doi:10.1016/j.cmet.2014.03.005. PMC 4058888. PMID 24703698.
  14. Yeo SH, Colledge WH (2018-04-26). "The Role of Kiss1 Neurons As Integrators of Endocrine, Metabolic, and Environmental Factors in the Hypothalamic-Pituitary-Gonadal Axis". Frontiers in Endocrinology. 9: 188. doi:10.3389/fendo.2018.00188. PMC 5932150. PMID 29755406.
  15. Navarro VM, Castellano JM, Fernández-Fernández R, Barreiro ML, Roa J, Sanchez-Criado JE, et al. (October 2004). "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. doi:10.1210/en.2004-0413. PMID 15242985.
  16. De Bond JP, Tolson KP, Nasamran C, Kauffman AS, Smith JT (October 2016). "Unaltered Hypothalamic Metabolic Gene Expression in Kiss1r Knockout Mice Despite Obesity and Reduced Energy Expenditure". Journal of Neuroendocrinology. 28 (10). doi:10.1111/jne.12430. PMID 27601011.
  17. Shahab M, Mastronardi C, Seminara SB, Crowley WF, Ojeda SR, Plant TM (February 2005). "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. Bibcode:2005PNAS..102.2129S. doi:10.1073/pnas.0409822102. PMC 548549. PMID 15684075.
  18. Plant TM, Ramaswamy S, Dipietro MJ (February 2006). "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. doi:10.1210/en.2005-1261. PMID 16282350.
  19. Richard N, Galmiche G, Corvaisier S, Caraty A, Kottler ML (March 2008). "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. doi:10.1111/j.1365-2826.2008.01653.x. PMID 18208554. S2CID 205345039.
  20. Neal-Perry G, Lebesgue D, Lederman M, Shu J, Zeevalk GD, Etgen AM (August 2009). "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. doi:10.1210/en.2008-1667. PMC 2717872. PMID 19423763.
  21. Funes S, Hedrick JA, Vassileva G, Markowitz L, Abbondanzo S, Golovko A, et al. (December 2003). "The KiSS-1 receptor GPR54 is essential for the development of the murine reproductive system". Biochemical and Biophysical Research Communications. 312 (4): 1357–1363. doi:10.1016/j.bbrc.2003.11.066. PMID 14652023.
  22. Martins CM, Fernandes BF, Antecka E, Di Cesare S, Mansure JJ, Marshall JC, Burnier MN (May 2008). "Expression of the metastasis suppressor gene KISS1 in uveal melanoma". Eye. 22 (5): 707–711. doi:10.1038/sj.eye.6703090. PMID 18219339.
  23. Cvetković D, Babwah AV, Bhattacharya M (September 2013). "Kisspeptin/KISS1R System in Breast Cancer". Journal of Cancer. 4 (8): 653–661. doi:10.7150/jca.7626. PMC 3805993. PMID 24155777.
  24. Guzman S, Brackstone M, Wondisford F, Babwah AV, Bhattacharya M (July 2019). "KISS1/KISS1R and Breast Cancer: Metastasis Promoter". Seminars in Reproductive Medicine. 37 (4): 197–206. doi:10.1055/s-0039-3400968. PMID 31972865.
  25. Navarro VM, Fernández-Fernández R, Castellano JM, Roa J, Mayen A, Barreiro ML, et al. (December 2004). "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. doi:10.1113/jphysiol.2004.072298. PMC 1665361. PMID 15486019.
  26. Plant TM, Ramaswamy S, Dipietro MJ (February 2006). "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. doi:10.1210/en.2005-1261. PMID 16282350.
  27. Silveira LG, Noel SD, Silveira-Neto AP, Abreu AP, Brito VN, Santos MG, et al. (May 2010). "Mutations of the KISS1 gene in disorders of puberty". The Journal of Clinical Endocrinology and Metabolism. 95 (5): 2276–2280. doi:10.1210/jc.2009-2421. PMC 2869552. PMID 20237166.
  28. Mikkelsen JD, Bentsen AH, Ansel L, Simonneaux V, Juul A (January 2009). "Comparison of the effects of peripherally administered kisspeptins". Regulatory Peptides. 152 (1–3): 95–100. doi:10.1016/j.regpep.2008.10.001. PMID 18940206. S2CID 6587724.
  29. Roseweir AK, Kauffman AS, Smith JT, Guerriero KA, Morgan K, Pielecka-Fortuna J, et al. (March 2009). "Discovery of potent kisspeptin antagonists delineate physiological mechanisms of gonadotropin regulation". The Journal of Neuroscience. 29 (12): 3920–3929. doi:10.1523/JNEUROSCI.5740-08.2009. PMC 3035813. PMID 19321788.

Further reading

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