Kisspeptin

Kisspeptin the product of the gene 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 is recently become clear that kisspeptin-GPR54 signaling has an important role in initiating GnRH secretion at puberty, the extent of which is an area of ongoing research.

This gene is a metastasis suppressor gene that suppresses metastases of melanomas and breast carcinomas without affecting tumorigenicity. The encoded protein may function to inhibit chemotaxis and invasion, attenuating metastasis in malignant melanomas. Studies suggest a putative role in the regulation of events downstream of cell-matrix adhesion, perhaps involving cytoskeletal reorganization. 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.

History
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.

Interestingly, the naming of the Kiss-1 gene and its product, kisspeptin, was made by the team of scientists who discovered the gene in Hershey, Pennsylvania, famous for its chocolate "kisses".

Kisspeptin Neurons
Kisspeptin expressing neurons are located in:
 * Anteroventral periventricular nucleus (AVPV)
 * Periventricular nucleus (PeN)
 * Anterodorsal preoptic nucleus (ADP)
 * The arcuate nucleus (Arc)

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 sited 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.