Kisspeptins (including kisspeptin-54 (KP-54), formerly known as metastin) are proteins encoded by the KISS1 gene in humans. Kisspeptins are ligands of the G-protein coupled receptor, 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. Gonadotropin-releasing hormone is released from the hypothalamus to act on the anterior pituitary triggering the release of luteinizing hormone (LH), and follicle stimulating hormone (FSH). These gonadotropic hormones lead to sexual maturation and gametogenesis. Disrupting GPR54 signaling can cause hypogonadotrophic hypogonadism in rodents and humans. The Kiss1 gene is located on chromosome 1. It is transcribed in the brain, adrenal gland, liver, gonads, and pancreas.
History In 1996, Danny Welch's lab in Hershey, Pennsylvania, isolated a cDNA from a cancer cell that was not able to undergo metastasis after the human chromosome 6 was added to the cell. This gene was named KISS1 because of the location of where it was discovered (Hershey, Pennsylvania, home of Hershey's Kisses). Introduction of this chromosome into the once active cancer cell inhibited it from spreading and the cDNA responsible was taken from that cell. The fact that KISS1 was responsible for this was proved when it was transfected into melanoma cells and yet again, metastasis was suppressed. Later, a breakthrough would occur not involving Kisspeptin, but with its receptor. Three years later in 1999, a G protein coupled receptor was identified in rat, cloned, and termed GPR54. Additionally, two years later, this receptor's ortholog in humans would be isolated. Using the identified receptors, endogenous ligands were isolated from cells (HEK293, B16-BL6, and CHO-K1 cells) that had these receptors inserted into them. The next step in the history of Kisspeptin involved revealing more of its pathways and the mechanism involved. Kisspeptin was found to play a role in hypogonadotropic hypogonadism in 2003, which was supported by several independent lab groups. A mutation in GPR54 was considered responsible for this abnormality because those who held this mutation, or were missing GPR54 altogether, had problems in gonadal development during puberty. Several other phenotypes related to this mutation included a lower concentration of sex steroid and gonadotropin in the circulating blood and even sterility. These observations prompted the research on how kisspeptin is involved during the beginning of puberty. This research led to the discovery that kisspeptin stimulates the neurons that were involved in the release of gonadotropin-releasing hormone (GnRH) and possibly may have some impact on the release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Today, much effort is being made to characterize the regulation of kisspeptin and its gene expression, as well as to more specifically determine the mechanism behind kisspeptin's action on GnRH and LH release.
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Hippocampal dentate gyrus
Kisspeptin is most notably expressed in the hypothalamus, but is also found in other areas of the brain including the hippocampal dentate gyrus. The hippocampus is known to integrate information on a person's spatial environment and memory. KISS1 is known to be expressed in the hippocampus. However, the levels of KISS1 mRNA expressed are decidedly lower than in the hypothalamus and amygdala. Studies have shown that the levels of KISS1 mRNA expressed in the hippocampus are proportional to less than half of the levels found in the hypothalamus. Despite this, it is suggested that expression of KISS1 is influenced by the gonad hormones similar to the hypothalamus. There is a high degree of expression of GPR54 in the hippocampus. The density of GPR54 is not discernable in pyramidal cells, but has high levels of expression in the granule cell layer. It is known to be found in specific nuclei and neurons.
Adrenal gland The neuropeptide kisspeptin plays an important role in reproduction, but also stimulates aldosterone secretion from the adrenal cortex. Kisspeptin is distributed from the adrenal cortex and it is transcribed in the neocortex. The exact nature of the expression of kisspeptins in human adrenal glands unfortunately has not been fully clarified yet and remains a large topic of research among many scientists.
Genomics Kisspeptin is a product of the KISS1 gene which is cleaved from an initial 145 amino acid protein to a 54 amino acid long peptide. This gene is located on the long arm of chromosome 1 (1q32) and has four exons of which the 5' and 3' exons only partly undergo translation. The KISS1 gene was first isolated as a tumor spreading gene by investigators and named metastin. Metastin is derived from the protein kisspeptin and is a natural ligand of the receptor known as GPR54. Different types made up of 14 and 13 amino acids have been isolated and they each share a common C-terminal sequence. 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. Among these conserved amino acids are arginine and phenylalanine residues, which are paired in this family of peptides. Also within this conserved family is a C-terminus that has an amide added to it. This family which kisspeptin includes prolactin releasing peptide and gonadotropin releasing inhibiting hormone. 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 used, and the encoded protein extends for an additional seven amino acid residues.
Structure
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