[Show abstract][Hide abstract] ABSTRACT: Kisspeptin and its receptor, GPR54, play a pivotal role in vertebrate reproduction. Recent advances in bioinformatic tools combined with comparative genomics have led to the identification of a large number of kisspeptin and GPR54 genes in a variety of vertebrate species. Genome duplications may have produced at least two isoforms of both ligand (KiSS1 and KiSS2) and receptor (GPR54-1 and GPR54-2). Additional isoforms of kisspeptin (KiSS1b) and GPR54 (GPR54-1b) have been found in an amphibian species, Xenopus (Silurana) tropicalis. Here, we describe the evolutionary lineages of these kisspeptin and GPR54 isoforms using genome synteny and phylogenetic analyses, and possible molecular interactions between kisspeptin and GPR54 subtypes based on ligand-receptor selectivity. Together, kisspeptin and GPR54 provide an excellent model for understanding molecular coevolution of the peptide ligand and GPCR pairs.
Annals of the New York Academy of Sciences 07/2010; 1200(1):67-74. DOI:10.1111/j.1749-6632.2010.05508.x · 4.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Kisspeptin and its receptor GPR54 play important roles in mammalian reproduction and cancer metastasis. Because the KiSS and GPR54 genes have been identified in a limited number of vertebrate species, mainly in mammals, the evolutionary history of these genes is poorly understood. In the present study, we have cloned multiple forms of kisspeptin and GPR54 cDNAs from a variety of vertebrate species. We found that fish have two forms of kisspeptin genes, KiSS-1 and KiSS-2, whereas Xenopus possesses three forms of kisspeptin genes, KiSS-1a, KiSS-1b, and KiSS-2. The nonmammalian KiSS-1 gene was found to be the ortholog of the mammalian KiSS-1 gene, whereas the KiSS-2 gene is a novel form, encoding a C-terminally amidated dodecapeptide in the Xenopus brain. This study is the first to identify a mature form of KiSS-2 product in the brain of any vertebrate. Likewise, fish possess two receptors, GPR54-1 and GPR54-2, whereas Xenopus carry three receptors, GPR54-1a, GPR54-1b, and GPR54-2. Sequence identity and genome synteny analyses indicate that Xenopus GPR54-1a is a human GPR54 ortholog, whereas Xenopus GPR54-1b is a fish GPR54-1 ortholog. Both kisspeptins and GPR54s were abundantly expressed in the Xenopus brain, notably in the hypothalamus, suggesting that these ligand-receptor pairs have neuroendocrine and neuromodulatory roles. Synthetic KiSS-1 and KiSS-2 peptides activated GPR54s expressed in CV-1 cells with different potencies, indicating differential ligand selectivity. These data shed new light on the molecular evolution of the kisspeptin-GPR54 system in vertebrates.