|Symbols||; HH13; KiSS-1|
|RNA expression pattern|
Kisspeptin (formerly known as metastin) is a protein that in humans is encoded by the KISS1 gene. Kisspeptin is a G-protein coupled receptor ligand for GPR54. Kiss1 was originally identified as a human metastasis suppressor gene that has the ability to suppress melanoma and breast cancer metastasis. Kisspeptin-GPR54 signaling has an important role in initiating secretion of gonadotropin-releasing hormone (GnRH) at puberty, the extent of which is an area of ongoing research.
Kisspeptins are a family of peptides encoded by the KiSS-1 gene. This gene is located on the long arm of chromosome 1 (1q32) and has four exons of which the 5' and 3' exons are only partly translated. The gene product is a 145 amino acid precursor peptide which is cleaved to 54 amino acids in length, which may be further truncated to 14, 13 or 10 amino acid carboxyl terminal fragments. These N-terminally truncated peptides are known as the kisspeptins and belong to a larger family of peptides known as RFamides which all share a common arginine-phenylalanine-NH2 motif at their C-terminus.
A polymorphism in the terminal exon of this mRNA results in two protein isoforms. An adenosine present at the polymorphic site represents the third position in a stop codon. When the adenosine is absent, a downstream stop codon is utilized and the encoded protein extends for an additional seven amino acid residues.
Sources and function
Studies suggest a putative role in the regulation of events downstream of cell-matrix adhesion, perhaps involving cytoskeletal reorganization.
The protein encoded by this gene is a metastasis suppressor of melanomas and breast cancers without affecting tumorigenicity. The encoded protein may function to inhibit chemotaxis and invasion, attenuating metastasis in malignant melanomas.
It is found in atherosclerotic plaques of the coronary arteries.
The receptor for kisspeptin, GPR54, was first identified as an orphan GPCR in rat in 1999. In 2001, a natural ligand for GPR54 was discovered, which was the product of the Kiss1 gene, originally identified as a human metastasis suppressor gene. Subsequent mutant studies led to the discovery that LOF mutations in GPR54 causes failure to progress through puberty in humans, due to hypogonadotropic hypogonadism. Thus, it was concluded that Kisspeptin-GPR54 signaling is essential to initiate gonadotropin (LH/FSH) secretion at puberty.
The original nomenclature of the KiSS-1 gene and its product, kisspeptin, may have been named with a bit of whimsy, to ensure everyone knew (or might guess) where it was discovered— in Hershey, Pennsylvania, the home of the chocolate "Hershey's Kisses" although in 2003, UK researchers discovered kisspeptin and they were not known to be eating imported chocolate at the time.
Kisspeptin expressing neurons are located in:
- Anteroventral periventricular nucleus (AVPV)
- Periventricular nucleus (PeN)
- Anterodorsal preoptic nucleus (ADP)
- The arcuate nucleus (Arc)
Kisspeptin-expressing neurons reside in the anteroventral periventricular nucleus and the arcuate nucleus, among others, and send projections into the MPOA, where there is an abundance of GnRH cell bodies. This anatomical evidence suggests that Kisspeptin fibers appear in close anatomical relationship to GnRH (parvicellular) neurons. In fact, Kisspeptin appears to act directly on GnRH neurons (via GPR54) to stimulate the secretion of GnRH.
However, for kisspeptin to be involved in the regulation of GnRH release, it must also be sensitive to circulating sex steroid levels, as it is established that steroids produced by the gonads exert regulatory effects on FSH and LH levels through GnRH mediation. Thus, there are at least two possible scenarios: that either kisspeptin neurons express sex steroid receptors themselves, or they receive input about circulating sex steroid levels from a different mechanism .
Coexpression imaging of Kiss-1 mRNA (using vector red) and steroid receptors determined that neurons that express KiSS-1 mRNA are targets for the action of sex steroids in both male and female mice.
Role in Puberty
The following evidence has been cited to support a role for kisspeptin in puberty:
- Animals with LOF mutations and targeted deletions of GPR54 fail to progress through puberty as a result of hypogonadotropic * hypogonadism (HH).
- Activation of GnRH neurons is the key event that initiates the onset of puberty.
- Peripheral administration of kisspeptin to prepubertal, 25-day-old female rats stimulates LH secretion and induces ovulation in the rat.
- If kisspeptins trigger puberty onset, one would expect to see an increase in KiSS-1 mRNA and/or GPR54 mRNA expression during this time. RT-PCR essays and semiquantitative results support this hypothesis.
- The electrophysiologic response of GnRH neurons to kisspeptins appears to change dramatically over the course of puberty.
Mechanism of Action
Kisspeptin appears to directly activate GnRH neurons. Evidence for this involves the persistence of a neural response to kisspeptin levels even in the presence of TTX, a neurotoxin that blocks nerve signals.
- Gramicidin-perforated patch recordings: approx. 30% of GnRH neurons respond to kisspeptin administration in prepubertal males, whereas 60% of GnRH neurons in adult mice responded.
- Because only adult mice respond to low doses of kisspeptin, it appears that GnRH neurons become developmentally activated by kisspeptin over the course of puberty.
- Kisspeptin induces production of LH and FSH, which are required for female's menstruation. Athletes may not undergo menstruation due to low fat levels; fat produces the hormone "Leptin", which induces production of "Kisspeptin".
- Messager S, Chatzidaki EE, Ma D, Hendrick AG, Zahn D, Dixon J, Thresher RR, Malinge I, Lomet D, Carlton MB, Colledge WH, Caraty A, Aparicio SA (2005). "Kisspeptin directly stimulates gonadotropin-releasing hormone release via G protein-coupled receptor 54". Proc. Natl. Acad. Sci. U.S.A. 102 (5): 1761–6. doi:10.1073/pnas.0409330102. PMC 545088. PMID 15665093.
- Lee JH, Miele ME, Hicks DJ, Phillips KK, Trent JM, Weissman BE, Welch DR (December 1996). "KiSS-1, a novel human malignant melanoma metastasis-suppressor gene". J. Natl. Cancer Inst. 88 (23): 1731–7. doi:10.1093/jnci/88.23.1731. PMID 8944003.
- Skorupskaite, K.; George, J. T.; Anderson, R. A. (2014). "The kisspeptin-GnRH pathway in human reproductive health and disease". Human Reproduction Update 20 (4): 485–500. doi:10.1093/humupd/dmu009. ISSN 1355-4786.
- "Entrez Gene: KISS1 KiSS-1 metastasis-suppressor".
- Mead EJ, Maguire JJ, Kuc RE, Davenport AP (January 2007). "Kisspeptins are novel potent vasoconstrictors in humans, with a discrete localization of their receptor, G protein-coupled receptor 54, to atherosclerosis-prone vessels". Endocrinology 148 (1): 140–7. doi:10.1210/en.2006-0818. PMID 17023533.
- Lee D, Nguyen T, O'Neill G, Cheng R, Liu Y, Howard A, Coulombe N, Tan C, Tang-Nguyen A, George S, O'Dowd B (1999). "Discovery of a receptor related to the galanin receptors". FEBS Lett 446 (1): 103–7. doi:10.1016/S0014-5793(99)00009-5. PMID 10100623.
- Kotani M, Detheux M, Vandenbogaerde A, Communi D, Vanderwinden J, Le Poul E, Brézillon S, Tyldesley R, Suarez-Huerta N, Vandeput F, Blanpain C, Schiffmann S, Vassart G, Parmentier M (2001). "The metastasis suppressor gene KiSS-1 encodes kisspeptins, the natural ligands of the orphan G protein-coupled receptor GPR54". J Biol Chem 276 (37): 34631–6. doi:10.1074/jbc.M104847200. PMID 11457843.
- Gottsch ML, Clifton DK, Steiner RA (January 2009). "From KISS1 to kisspeptins: An historical perspective and suggested nomenclature". Peptides 30 (1): 4–9. doi:10.1016/j.peptides.2008.06.016. PMC 2683679. PMID 18644415.