The metastasis suppressor gene KiSS-1 encodes kisspeptins, the natural ligands of the orphan G protein-coupled receptor GPR54

Natural peptides displaying agonist activity on the orphan G protein-couple d receptor GPR54 were isolated from human placenta. These 54-, 14,- and 13- amino acid peptides, with a common RF-amide C terminus, derive from the pro duct of KiSS-1, a metastasis suppressor gene for melanoma cells, and were t herefore designated kisspeptins. They bound with low nanomolar affinities t o rat and human GPR54 expressed in Chinese hamster ovary K1 cells and stimu lated PIP2 hydrolysis, Ca2+ mobilization, arachidonic acid release, ERK1/2 and p38 MAP kinase phosphorylation, and stress fiber formation but inhibite d cell proliferation. Human GPR54 was highly expressed in placenta, pituita ry, pancreas, and spinal cord, suggesting a role in the regulation of endoc rine function. Stimulation of oxytocin secretion after kisspeptin administr ation to rats confirmed this hypothesis.