General

The metastin peptide was originally identified in 1996 from a metastasis suppressor gene in malignant melanoma, KiSS-1. Subsequently four biologically active cleavage products of the KiSS-1 gene product have been identified and termed the kisspeptins, kisspeptin-54 (KP-54, previously known as metastin; 1-54), kisspeptin-14 (KP-14; 41-54), kisspeptin-13 (KP-13; 42-54) and kisspeptin-10 (KP-10; 45-54). The KiSS-1 gene is located on chromosome 1q32 in human and has four exons, encoding a 144-residue precursor for the kisspeptins. Orthologues have been identified in various vertebrate species including rat and mouse. The highest expression of the kisspeptins precursor is in placenta, although it has been detected in other peripheral tissues such as the intestine, testes, ovary and liver at lower levels. Additionally it has been detected in a variety of brain regions including the hypothalamus, caudate nucleus and putamen. In 2001 the kisspeptins were paired with the orphan G-protein coupled receptor (GPCR) kisspeptin (GPR54, metastin receptor, AXOR12, hOT7T175).

Receptor structure

The kisspeptin receptor is a member of the rhodopsin-type receptor superfamily. It consists of 398 amino acids in human and has a molecular weight of 42.6 kDa. It contains seven putative transmembrane spanning regions of 18-23 hydrophobic amino acids, typical of GPCRs. There are three potential phosphorylation sites at the N-terminus of the kisspeptin receptor precursor. The kisspeptin receptor gene is encoded by 5 exons and in human is located on chromosome 19p13.3.

Receptor signalling

Activation of the kisspeptin receptor primarily results in signal transduction via G_q/G₁₁ G-proteins, which stimulate the phospholipase C enzyme system resulting in downstream Ca²⁺ mobilisation. In CHO cells a strong stimulation of MAP kinases ERK1 and ERK2, along with a weaker stimulation of p38 MAP kinase phosphorylation has also been noted. Additionally activation of the kisspeptin receptor has been shown to stimulate arachidonic acid release [1].

Physiology

The kisspeptin receptor is most highly expressed within the pancreas and placenta, but has also been identified in variety of other peripheral tissues including small intestine, kidney, lung, liver and heart. In addition it has been shown to be widely distributed throughout the brain, where it is most highly expressed in the hypothalamic and amygdaloid nuclei. Initially the kisspeptins, acting through the kisspeptin receptor, were identified as potent inhibitors of metastasis in a variety of cancer cell types including thyroid and pancreatic cancer cells. There are distinct similarities between the invasiveness of cancer metastases, and the invasiveness of the placenta into the uterus. The kisspeptin receptor has been identified in human trophoblasts and has a role in the inhibition of trophoblast migration during placentation. In 2003 genetic linkage analysis identified a consanguineous family with idiopathic hypogonadotrophic hypogonadism (IHH) resulting from a mutation in the kisspeptin receptor gene (Leu¹⁴⁸ to Ser). Subsequently three other single nucleotide polymorphisms (SNPs) in the kisspeptin receptor gene leading to IHH, as well as one splice variant in exon 5 have been identified. Interestingly kisspeptin receptor knockout mouse studies mimic the human natural variants resulting in IHH. Activation of the kisspeptin receptor by kisspeptins has been shown to stimulate secretion of LH and FSH, an effect abolished in knockout mice.

Pharmacology

Cleavage products of the KISS-1 peptide gene have been identified as full agonists at the kisspeptin receptor and are equipotent for both the human and rat receptors. The longest biologically active peptide is kisspeptin-54 and the shortest kisspeptin-10. As this is a novel receptor system the relative potencies of each of the kisspeptins varies between reports, however consensus suggests that the most potent naturally occurring fragment is kisspeptin-10, with cited potency, in terms of K_i, ranging from 0.042 nM to 2.35 nM. No antagonist for this receptor has currently been identified.

1. Kotani M, Detheux M, Vandenbogaerde A, Communi D, Vanderwinden JM, Le Poul E, Brézillon S, Tyldesley R, Suarez-Huerta N, Vandeput F et al.. (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. [PMID:11457843]