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. It recently became clear that 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.
In the brain this gene is transcribed within the hippocampal dentate gyrus. It is also transcribed in the vascular endothelium.
It is transcribed within the neocortex of the adrenal gland with higher levels in foetal compared to adult tissues. Kisspeptin-54 can stimulate secretion of aldosterone.
It is transcribed in the pancreas within the islet cells and where it can stimulate release of insulin.
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. Following 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 man, 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".
Kisspeptin expressing neurons are located in:
Kisspeptin neurons reside in nuclei such as Arc and AVPV 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 steroid levels within the circulation, as it has already been established that steroids produced by the gonads exert regulatory effects on FSH and LH levels through GnRH mediation. Therefore, there are (at least) two possible scenarios: That either kisspeptin neurons express steroid receptors (such as ERα, ERβ, and AR) themselves, or they receive input from another mechanism about circulating steroid levels.
Coexpression imaging of Kiss-1 mRNA (using vector red) and steroid receptors determined that KiSS-1 neurons are direct target for the action of sex steroids in both the male and female mouse.
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".
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- Kisspeptin.org is a dedicated web portal for Kisspeptin researchers. link title. http://www.kisspeptin.org.