Structure, synthesis, and phylogeny of kisspeptin and its receptor.

The kisspeptin system is considered to be essential for successful mammalian reproduction. In addition to the Kiss1 peptide, Kiss2, the product of kiss2 (the kiss1 paralogue), has also been shown to activate kisspeptin receptor signaling pathways in nonmammalian species. Furthermore, in nonmammalian species, there are two subtypes of receptors, Gpr54-1 (known as GPR54 or Kiss1R in mammals) and Gpr54-2. Although complete understanding of the two kisspeptin-two kisspeptin receptor systems in vertebrates is not so simple, a careful examination of the phylogeny of their genes may provide insights into the functional generality and differences among the kisspeptin systems in different animal phyla. In this chapter, we first discuss the structure of kisspeptin ligands, Kiss1 and Kiss2, and their characteristics as physiologically active peptides. Then, we discuss the evolutionary traits of kiss1 and kiss2 genes and their receptor genes, gpr54-1 and gpr54-2. It appears that each animal species has selected either kiss1 or kiss2 rather randomly, leading us to propose that some of the important characteristics of kisspeptin neurons, such as steroid sensitivity and the anatomical relationship with the hypophysiotropic GnRH1 neurons, may be the keys to understanding the general functions of different kisspeptin neuronal populations throughout vertebrates. Species differences in kiss1/kiss2 may also provide insights into the evolutionary mechanisms of paralogous gene-expressing neuronal systems. Finally, because kisspeptins belong to one of the members of the RFamide peptide families, we discuss the functional divergence of kisspeptins from the other RFamide peptides, which may be explained from phylogenetic viewpoints.