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Fundamentals of Kisspeptin Biology

Please find articles on the history of kisspeptin and its recptor as well as realted genetics, structural aspects and signalling.

Kisspeptins are peptide products of the KiSS-1 gene, which was discovered by Lee et al. in 1996 as a metastasis suppressing gene in malignant melanoma cells (Lee et al., 1996). As it was discovered in Hershey, the gene was named after Hershey’s famous chocolate kisses.

Kisspeptins are the natural ligands for the orphan GPCR known as gpr-54 in rat (Lee et al., 1999) and AXOR12 in humans (Muir et al., 2001). However, for ease, throughout the rest of this Wiki only gpr-54 (or its newer name kiss -1R) designation will be used. Gpr-54 is a 396 amino acid receptor and is a member of the rhodopsin family/Class A g-protein coupled receptors.

The human KiSS-1 gene was first discovered in 1996 and has since been mapped to the long arm of chromosome 1 at 1q32 by radiation hybrid mapping and fluorescent in-situ hybridisation (FISH). This has been confirmed by genome sequencing.

The KiSS-1 gene encodes a large polypeptide consisting of 145 amino acids, known as the pre-peptide to kisspeptins. This pre-peptide contains a 19 amino acid leader sequence that directs the protein into the endoplasmic reticulum (ER) and which gives rise to a secretory precursor protein of 126 amino acids which is proteolytically cleaved and modified to form a C-terminal amide moiety in the Golgi membrane network (Takino et al., 2003).

Gpr-54 is a member of the rhodopsin-like or Class A family of G-protein coupled receptors located on human chromosome 19p13.3. GPCRs are membrane bound receptors that contain seven hydrophobic transmembrane domains each containing between 25-40 amino acids.

To date a limited number of signalling pathways have been evaluated for the kisspeptin/gpr-54 pathway. These have predominantly been in relation to two areas of kisspeptin action: GnRH secretion within the GnRH neuron and kisspeptins actions in cancer metastasis.

KiSS-1 neurons directly contact GnRH neurons expressing gpr-54 to cause secretion of GnRH into the hypophyseal portal blood to act on the pituitary.