Metastin (45-54)

Metastasis suppressor peptide as the ligand of orphan receptor

Searching for ligands to orphan receptors is one of the most popular methods to discover novel endogenous peptides. Human orphan receptor orthologs, hOT7T175, AXOR12 and GPR54, show some sequence similarity to the galanin receptor. However, the CHO cells expressing the hOT7T175 do not respond to galanin and galanin-like peptide[Nature, 411, 613 (2001)]. Three groups have reported their endogenous ligand almost simultaneously to be the same part of the metastasis suppressor gene KiSS-1 product, the KiSS-1 gene product (68-121) amide. This peptide, designated as metastin[Nature, 411, 613 (2001)], KiSS-1(112-121)[J. Biol. Chem., 276, 28969 (2001).] or kisspeptin-54 [J. Biol. Chem., in press (Online July 16; epub M10484720)], together with some truncated peptides were isolated from placental extracts, all of which have the same RF amide C-terminus. Metastin itself attenuates pulmonary metastasis of hOT7T175-transfected B16-BL6 melanomas[Nature, 411, 613 (2001)].


Additionally, metastin possesses a potent activity of inducing an increase in Ca²⁺ concentration in the CHO cells expressing hOT7T175. The structure-activity relationship study of this peptide revealed the importance of the C-terminal amide structure. Moreover, the C-terminal 10 amino acid residue peptide, metastin (45-54) (or kisspeptin-10), was found to show ten times more potent activity than the parent peptide. This peptide fragment possesses a low Ki value in the pM to nM range in competitive binding assay. These activities are specific to metastin (or kisspeptin) because no responses were obtained upon using other RF amide family peptides. Concerning in vivo activity, stimulation of oxytocin secretion was observed in rat at a dose of 25 mg of kisspeptin-10.

Further studies utilizing metastin (45-54) (or kisspeptin-10) might help to evaluate unknown functional roles which includes clarification of the mechanism of its activity as a metastasis suppressor.