Biology:KiSS1-derived peptide receptor

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Short description: Mammalian protein found in Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example


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.[10]

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.[17] 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

References

  1. ↑ "Discovery of a receptor related to the galanin receptors". FEBS Letters 446 (1): 103–107. March 1999. doi:10.1016/S0014-5793(99)00009-5. PMID 10100623. 
  2. ↑ "Metastasis suppressor gene KiSS-1 encodes peptide ligand of a G-protein-coupled receptor". Nature 411 (6837): 613–617. May 2001. doi:10.1038/35079135. PMID 11385580. Bibcode: 2001Natur.411..613O. 
  3. ↑ "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. doi:10.1074/jbc.M102743200. PMID 11387329. 
  4. ↑ "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. doi:10.1074/jbc.M104847200. PMID 11457843. 
  5. ↑ "KiSS-1 and GPR54 at the pituitary level: overview and recent insights". Peptides 30 (1): 123–129. January 2009. doi:10.1016/j.peptides.2008.09.015. PMID 18948153. 
  6. ↑ "Kisspeptin excites gonadotropin-releasing hormone neurons through a phospholipase C/calcium-dependent pathway regulating multiple ion channels". Endocrinology 149 (9): 4605–4614. September 2008. doi:10.1210/en.2008-0321. PMID 18483150. 
  7. ↑ "The role of kisspeptin in the control of gonadotrophin secretion". Human Reproduction Update 15 (2): 203–212. 2008-11-05. doi:10.1093/humupd/dmn058. PMID 19109311. 
  8. ↑ "Impaired kisspeptin signaling decreases metabolism and promotes glucose intolerance and obesity". The Journal of Clinical Investigation 124 (7): 3075–3079. July 2014. doi:10.1172/jci71075. PMID 24937427. 
  9. ↑ "Glucagon regulates hepatic kisspeptin to impair insulin secretion". Cell Metabolism 19 (4): 667–681. April 2014. doi:10.1016/j.cmet.2014.03.005. PMID 24703698. 
  10. ↑ 10.0 10.1 "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. doi:10.3389/fendo.2018.00188. PMID 29755406. 
  11. ↑ "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. doi:10.1210/en.2004-0413. PMID 15242985. 
  12. ↑ "Unaltered Hypothalamic Metabolic Gene Expression in Kiss1r Knockout Mice Despite Obesity and Reduced Energy Expenditure". Journal of Neuroendocrinology 28 (10). October 2016. doi:10.1111/jne.12430. PMID 27601011. PMC 5083214. https://escholarship.org/uc/item/09b2p5bs. 
  13. ↑ "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. doi:10.1073/pnas.0409822102. PMID 15684075. Bibcode: 2005PNAS..102.2129S. 
  14. ↑ "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. doi:10.1210/en.2005-1261. PMID 16282350. 
  15. ↑ "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. doi:10.1111/j.1365-2826.2008.01653.x. PMID 18208554. 
  16. ↑ "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. doi:10.1210/en.2008-1667. PMID 19423763. 
  17. ↑ 17.0 17.1 "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. doi:10.1016/j.bbrc.2003.11.066. PMID 14652023. 
  18. ↑ "Expression of the metastasis suppressor gene KISS1 in uveal melanoma". Eye 22 (5): 707–711. May 2008. doi:10.1038/sj.eye.6703090. PMID 18219339. 
  19. ↑ "Kisspeptin/KISS1R System in Breast Cancer". Journal of Cancer 4 (8): 653–661. September 2013. doi:10.7150/jca.7626. PMID 24155777. 
  20. ↑ "KISS1/KISS1R and Breast Cancer: Metastasis Promoter". Seminars in Reproductive Medicine 37 (4): 197–206. July 2019. doi:10.1055/s-0039-3400968. PMID 31972865. 
  21. ↑ "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. doi:10.1113/jphysiol.2004.072298. PMID 15486019. 
  22. ↑ "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. doi:10.1210/en.2005-1261. PMID 16282350. 
  23. ↑ "Mutations of the KISS1 gene in disorders of puberty". The Journal of Clinical Endocrinology and Metabolism 95 (5): 2276–2280. May 2010. doi:10.1210/jc.2009-2421. PMID 20237166. 
  24. ↑ "Comparison of the effects of peripherally administered kisspeptins". Regulatory Peptides 152 (1–3): 95–100. January 2009. doi:10.1016/j.regpep.2008.10.001. PMID 18940206. 
  25. ↑ "Discovery of potent kisspeptin antagonists delineate physiological mechanisms of gonadotropin regulation". The Journal of Neuroscience 29 (12): 3920–3929. March 2009. doi:10.1523/JNEUROSCI.5740-08.2009. PMID 19321788. 

Further reading

External links

This article incorporates text from the United States National Library of Medicine, which is in the public domain.



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