Kisspeptin

Kisspeptin is the common name for a family of peptides. They are cut from the protein made by the KISS1 gene. The gene was first described in melanoma cells as a metastasis suppressor. It was named KiSS-1 (Lee et al., 1996). Five years later, three groups found that its product is cut into peptides. These peptides activate the orphan receptor GPR54, now called KISS1R. One is a 54-residue peptide named metastin (Ohtaki et al., 2001).

The others are shorter C-terminal fragments of 14, 13 and 10 residues. They bind the receptor with low nanomolar affinity (Kotani et al., 2001; Muir et al., 2001). The material sold as kisspeptin for lab work is normally kisspeptin-10. This is the C-terminal decapeptide. It is also written KP-10 or metastin (45-54).

Sequence and aliases come from PubChem.

Published work on kisspeptin falls into six areas. Each summary below states the model used.

Receptor pharmacology in cell culture

One study purified peptides from human placenta. They bound rat and human GPR54 with low nanomolar affinity. The receptors were expressed in Chinese hamster ovary cells. The peptides triggered phosphoinositide hydrolysis, calcium mobilization and MAP kinase phosphorylation. They also inhibited proliferation of the transfected cells (Kotani et al., 2001). A parallel report cloned the same receptor as AXOR12.

It found the highest receptor transcript levels in brain, pituitary and placenta (Muir et al., 2001). The C-terminal amide is needed for activity. Matrix metalloproteinases were used to cut the decapeptide between Gly and Leu. The cut peptide could no longer act on the receptor (Takino et al., 2003).

Human genetics of the KISS1R pathway

Two 2003 reports linked loss-of-function changes in GPR54 to absent pubertal development. One mapped a consanguineous family to chromosome 19p13. It found a homozygous 155-nucleotide deletion in GPR54 in all five affected siblings (de Roux et al., 2003). The other found an L148S change in one pedigree. It also found compound changes in an unrelated case. The variant receptor showed lower inositol phosphate accumulation in transfected cells. The same paper found the matching phenotype in Gpr54-deficient mice (Seminara et al., 2003).

Gonadotropin release in rodent models

In mice, kisspeptin-10 and kisspeptin-54 were given into the lateral cerebral ventricle. Both raised luteinizing hormone (LH). Giving a GnRH antagonist first blocked this effect. KISS1 transcripts were mapped to hypothalamic nuclei involved in gonadotropin control (Gottsch et al., 2004). In adult male rats, kisspeptin-10 was given both centrally and peripherally. It raised LH, follicle-stimulating hormone (FSH) and total testosterone. The peptide also released LHRH from hypothalamic explants.

Isolated pituitary fragments did not respond (Thompson et al., 2004). A parallel rat study found that systemic KiSS-1 peptide also raised LH, and read part of that response as a direct action at the pituitary (Navarro et al., 2005). Double-label in situ hybridization found that 77 percent of GnRH neurons co-express the receptor transcript (Irwig et al., 2004).

Primate and sheep models

In sheep, kisspeptin was given into the cerebral ventricle. Direct measurement showed that it released GnRH into cerebrospinal fluid. Serum LH rose at the same time. Kisspeptin had no effect in Gpr54-null mice. This places the action at the GnRH neuron (Messager et al., 2005). In agonadal juvenile monkeys, kisspeptin-10 triggered a GnRH discharge. A GnRH-receptor antagonist abolished it.

Hypothalamic KISS1 transcript levels also rose across the pubertal transition (Shahab et al., 2005). Continuous infusion in the same model gave a brisk response for about three hours. Then the response fell sharply. A later challenge with the peptide no longer worked, while GnRH itself still did. The authors read this as receptor desensitization (Seminara et al., 2006).

Human clinical studies

A few academic groups have run controlled studies in volunteers. In one, kisspeptin-54 was compared with saline in six healthy men. It raised LH, FSH and testosterone. The measured plasma half-life was near 28 minutes (Dhillo et al., 2005). Kisspeptin-10 raised LH in healthy men. Giving it continuously increased pulse frequency and secretory burst mass (George et al., 2011). A separate group reported that giving the peptide once advanced the next LH pulse. It then delayed the following pulse by roughly one interpulse interval.

The authors read this as resetting the hypothalamic pulse generator (Chan et al., 2011). Responses differ by sex and cycle phase. Women in the follicular phase showed no measurable gonadotropin response at the amounts tested. Men, and women in the preovulatory phase, did respond (Jayasena et al., 2011). A head-to-head comparison was run in healthy men. It found kisspeptin-10 and kisspeptin-54 broadly similar to each other. Both were weaker than GnRH (Jayasena et al., 2015).

Metastasis, placenta and peripheral tissues

Full-length KiSS-1 complementary DNA was transfected into melanoma cells. This suppressed metastasis in mice in an expression-dependent way. It did not block tumor formation (Lee et al., 1996). In primary human trophoblasts, kisspeptin-10 raised calcium inside the cells. It inhibited migration in explant and transwell assays. Proliferation did not change (Bilban et al., 2004). Receptor and peptide have also been found in human aorta, coronary artery and umbilical vein.

There, the peptides constricted isolated vessel rings (Mead et al., 2007). They have also been found in pancreatic islets. Reported effects on insulin secretion there have gone in both directions. The direction depended on the preparation (Hauge-Evans et al., 2006; Bowe et al., 2009). A broad review of the field covers these strands together (Pinilla et al., 2012).