Kisspeptin-10: The Metastin Fragment in the Research Literature

Research-use-only context. This article summarizes published third-party scientific literature and laboratory practice. It is not medical advice, not a therapeutic or performance claim, and not a usage guide. US Prime Peptides products are supplied strictly for in vitro laboratory research and are not for human or veterinary use.

Kisspeptin-10 is the ten-residue C-terminal fragment of metastin, the 54-amino-acid product of the human KISS1 gene, and the shortest natural fragment that fully activates the receptor GPR54 (now named KISS1R). This article explains the fragment nomenclature, traces the 1996 to 2005 discovery papers, summarizes what cell, rodent, sheep and human physiology studies have measured, and sets out the compound's status as an unapproved research chemical.

What kisspeptin-10 is: a fragment of a fragment

Human kisspeptin-10 is the decapeptide amide Tyr-Asn-Trp-Asn-Ser-Phe-Gly-Leu-Arg-Phe-NH₂ (YNWNSFGLRF-NH₂), with the formula C₆₃H₈₃N₁₇O₁₄, a molecular weight of 1302.4, PubChem CID 25240297 and CAS 374675-21-5. It is also written metastin(45-54), because it is residues 45 through 54 of the 54-residue peptide metastin. The naming chain runs: the KISS1 gene encodes a 145-residue precursor; proteolytic processing releases a 54-residue C-terminally amidated peptide (kisspeptin-54, also called metastin); further cleavage yields 14-, 13- and 10-residue fragments that share the same C-terminus. All of them end in Arg-Phe-NH₂, which places kisspeptins in the RF-amide peptide family alongside neuropeptide FF and the RFRPs. The amidated C-terminus is essential; the free acid is far less active at the receptor, so a certificate should state the amide explicitly, as explained in how to read a peptide sequence.

One species detail matters for ordering and for reading papers: rodent kisspeptin-10 ends in Arg-Tyr-NH₂ rather than Arg-Phe-NH₂, so a mouse study and a human-sequence vial are not the same molecule. A certificate for the human sequence should show a mass consistent with the Phe-terminated decapeptide.

Discovery: a melanoma gene, then a placental peptide

The gene came first. In 1996, Lee and colleagues at Penn State reported in the Journal of the National Cancer Institute that transferring human chromosome 6 into a metastatic melanoma cell line suppressed metastasis without affecting tumor growth, and they isolated the responsible transcript, naming it KiSS-1. For five years it was a gene with no known product. Then three groups published in 2001. Ohtaki and colleagues at Takeda, in Nature, isolated a 54-residue amidated peptide from human placenta as the endogenous ligand of the orphan receptor hOT7T175, named it metastin, and reported that it inhibited chemotaxis and invasion of receptor-transfected CHO cells in vitro and reduced lung metastases of receptor-transfected B16-BL6 melanoma cells in mice. Kotani and colleagues in Brussels, in the Journal of Biological Chemistry, isolated the 54-, 14- and 13-residue forms, named them kisspeptins, and showed low-nanomolar binding to rat and human GPR54 in CHO-K1 cells with downstream PIP₂ hydrolysis, calcium mobilization, arachidonic acid release and ERK1/2 and p38 phosphorylation. Muir and colleagues at GlaxoSmithKline, also in the Journal of Biological Chemistry, described the same receptor as AXOR12 and showed it was activated by KiSS-1 peptides.

So by the end of 2001 the field had a gene, a family of amidated peptides, and a receptor called variously GPR54, hOT7T175 and AXOR12. The receptor is now formally KISS1R, and the naming article covers why such multiplicity is normal for peptides discovered by parallel groups.

The receptor: GPR54 / KISS1R and the reproductive-axis findings

KISS1R is a class A G protein-coupled receptor that couples predominantly through G_q/11, phospholipase C, inositol trisphosphate and intracellular calcium, the pathway Kotani's 2001 cell work first mapped. The GPCR primer explains the shared machinery. What made the receptor famous was human genetics. In 2003, two independent papers, de Roux and colleagues in Proceedings of the National Academy of Sciences and Seminara and colleagues in the New England Journal of Medicine, reported that families with inherited hypogonadotropic hypogonadism carried loss-of-function variants in GPR54, and the Seminara study added that Gpr54-knockout mice failed to progress through puberty despite normal GnRH neuron anatomy.

The 2005 PNAS paper by Messager and colleagues then located the mechanism. They found Gpr54 transcripts co-expressed with GnRH in mouse hypothalamic neurons, showed that kisspeptin raised circulating LH and FSH in wild-type mice but had no effect in Gpr54-null mice, and measured a direct rise in GnRH in the cerebrospinal fluid of sheep after kisspeptin was placed into the cerebral ventricles. Together these studies established kisspeptin signaling through KISS1R as an upstream input to GnRH neurons, which is why kisspeptin-10 research is usually paired with the GnRH decapeptide covered in the gonadorelin overview. The 2012 Physiological Reviews survey by Pinilla and colleagues, which runs to more than 80 pages, remains the standard map of the rodent, sheep and primate literature.

Structure-activity work: what the ten residues need

Because kisspeptin-10 is the smallest fully active natural fragment, medicinal chemists used it as the template for both shorter agonists and the first antagonists. Niida and colleagues at Kyoto University reported in Bioorganic and Medicinal Chemistry Letters in 2006 that metastin(45-54) could be downsized further while keeping GPR54 agonist activity in cell assays, and a companion Bioorganic and Medicinal Chemistry paper by Tomita and colleagues the same year mapped the structure-activity relationship around a pentapeptide core, identifying a non-natural analog (H-Amb-Nal(2)-Gly-Leu-Arg-Trp-NH₂) with the highest agonist potency reported at the time. The practical lesson for a research lab is that the C-terminal Leu-Arg-Phe-NH₂ region carries the receptor recognition, and the aromatic residues on either side tune potency.

Antagonists came from the same scaffold. Roseweir and colleagues reported in the Journal of Neuroscience in 2009 that systematic amino-acid substitutions in kisspeptin-10 produced potent, specific KISS1R antagonists. In their hands a selected antagonist inhibited the firing of GnRH neurons in mouse brain slices, reduced pulsatile GnRH secretion in pubertal female monkeys, and blocked the post-castration rise in LH in sheep, rats and mice. Those are tool-compound findings: they define what the kisspeptin input does in each species by removing it, and they are the reason kisspeptin-10 analogs appear in neuroendocrine labs as probes rather than as end products.

Human physiology studies and what they do not establish

Kisspeptin fragments have been used as probes in a small number of academic human physiology protocols, including a 2005 Journal of Clinical Endocrinology and Metabolism study of kisspeptin-54 and a 2011 study in the same journal of kisspeptin-10, both of which measured pituitary hormone pulsatility with frequent sampling under ethics-board supervision. These are mechanism experiments on the hypothalamic-pituitary axis; they are not drug trials, they describe no product, and they do not establish any clinical use. No kisspeptin fragment holds marketing approval from the FDA or any other regulator, and none appears in Drugs@FDA. Kisspeptin-54 has been evaluated in investigational clinical studies by academic groups, but investigational status is not approval. The FDA status table lists kisspeptin-10 as "never submitted."

Chemistry notes for the research vial

Kisspeptin-10 is a short, moderately hydrophobic peptide with three features that affect storage and analysis. It carries a tryptophan at position 3, which is the residue most prone to oxidation in solution and under light. It has two asparagines, at positions 2 and 4, and the Asn-Ser and Asn-Trp junctions can deamidate slowly at neutral or basic pH, shifting the mass by one dalton and producing an isoaspartate shoulder on HPLC. And the Trp-Phe-Leu-Phe content makes it adsorb to standard polypropylene at low concentration, so low-binding tubes are standard; see why peptides stick to plastic. For Kisspeptin-10 10 mg the lot-matched certificate reports identity by mass spectrometry against the expected mass of 1302.4, HPLC purity, net peptide content, endotoxin, sterility and heavy metals, and the label mass refers to the lyophilized fill, not to net peptide. The human sequence and the C-terminal amide should both be visible on that document.

Frequently Asked Questions

What is the difference between kisspeptin-10 and kisspeptin-54?

Kisspeptin-54, also called metastin, is the full 54-residue peptide processed from the KISS1 precursor. Kisspeptin-10 is its last ten residues (positions 45-54). Both end in Arg-Phe-NH₂ and both activate KISS1R; the decapeptide is the smallest natural fragment that does so fully, which is why it is the common research reagent.

What receptor does kisspeptin-10 bind?

Kisspeptin-10 binds KISS1R, the receptor originally published as GPR54, AXOR12 and hOT7T175 by three groups in 2001. It is a G_q-coupled class A GPCR, and in cell assays its activation produces PIP₂ hydrolysis, calcium release and ERK phosphorylation.

Is kisspeptin-10 an approved drug?

No. No kisspeptin fragment is approved by the FDA or by any other regulator, and none is listed in Drugs@FDA. Published human studies are academic physiology experiments, and kisspeptin-54 has appeared in investigational trials, but investigational is not approved. A research vial is a laboratory reagent only.

Why does the KISS1 gene have that name?

Lee and colleagues isolated it in 1996 as a human melanoma metastasis-suppressor gene at Penn State in Hershey, Pennsylvania, and the "KiSS" name alludes to the chocolate Kisses made in that town. The "metastin" name given to the 54-residue peptide in 2001 reflects the same metastasis-suppression origin.

Citations

1. Lee JH, Miele ME, Hicks DJ, et al. KiSS-1, a novel human malignant melanoma metastasis-suppressor gene. J Natl Cancer Inst. 1996;88:1731-1737. PMID 8944003
2. Ohtaki T, Shintani Y, Honda S, et al. Metastasis suppressor gene KiSS-1 encodes peptide ligand of a G-protein-coupled receptor. Nature. 2001;411:613-617. PMID 11385580
3. Kotani M, Detheux M, Vandenbogaerde A, et al. The metastasis suppressor gene KiSS-1 encodes kisspeptins, the natural ligands of the orphan G protein-coupled receptor GPR54. J Biol Chem. 2001;276:34631-34636. PMID 11457843
4. Muir AI, Chamberlain L, Elshourbagy NA, et al. AXOR12, a novel human G protein-coupled receptor, activated by the peptide KiSS-1. J Biol Chem. 2001;276:28969-28975. PMID 11387329
5. de Roux N, Genin E, Carel JC, Matsuda F, Chaussain JL, Milgrom E. Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54. Proc Natl Acad Sci USA. 2003;100:10972-10976. PMID 12944565
6. Seminara SB, Messager S, Chatzidaki EE, et al. The GPR54 gene as a regulator of puberty. N Engl J Med. 2003;349:1614-1627. PMID 14573733
7. Messager S, Chatzidaki EE, Ma D, et al. Kisspeptin directly stimulates gonadotropin-releasing hormone release via G protein-coupled receptor 54. Proc Natl Acad Sci USA. 2005;102:1761-1766. PMID 15665093
8. Niida A, Wang Z, Tomita K, et al. Design and synthesis of downsized metastin (45-54) analogs with maintenance of high GPR54 agonistic activity. Bioorg Med Chem Lett. 2006;16:134-137. PMID 16242330
9. Tomita K, Niida A, Oishi S, et al. Structure-activity relationship study on small peptidic GPR54 agonists. Bioorg Med Chem. 2006;14:7595-7603. PMID 16879969
10. Roseweir AK, Kauffman AS, Smith JT, et al. Discovery of potent kisspeptin antagonists delineate physiological mechanisms of gonadotropin regulation. J Neurosci. 2009;29:3920-3929. PMID 19321788
11. Dhillo WS, Chaudhri OB, Patterson M, et al. Kisspeptin-54 stimulates the hypothalamic-pituitary gonadal axis in human males. J Clin Endocrinol Metab. 2005;90:6609-6615. PMID 16174713
12. George JT, Veldhuis JD, Roseweir AK, et al. Kisspeptin-10 is a potent stimulator of LH and increases pulse frequency in men. J Clin Endocrinol Metab. 2011;96:E1228-E1236. PMID 21632807
13. Pinilla L, Aguilar E, Dieguez C, Millar RP, Tena-Sempere M. Kisspeptins and reproduction: physiological roles and regulatory mechanisms. Physiol Rev. 2012;92:1235-1316. PMID 22811428
14. PubChem. Kisspeptin-10 (human), CID 25240297. PubChem

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