title: Molecular evolution of multiple forms of kisspeptins and GPR54 receptors in vertebrates.
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.
authors.affiliation: Laboratory of G Protein-Coupled Receptors, Graduate School of Medicine, Korea University, Seoul, Korea.
authors.forename: Yeo Reum
authors.initials: YR
authors.lastname: Lee
authors.forename: Kenta
authors.initials: K
authors.lastname: Tsunekawa
authors.forename: Mi Jin
authors.initials: MJ
authors.lastname: Moon
authors.forename: Haet Nim
authors.initials: HN
authors.lastname: Um
authors.forename: Jong-Ik
authors.initials: JI
authors.lastname: Hwang
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Osugi
authors.forename: Naohito
authors.initials: N
authors.lastname: Otaki
authors.forename: Yuya
authors.initials: Y
authors.lastname: Sunakawa
authors.forename: Kyungjin
authors.initials: K
authors.lastname: Kim
authors.forename: Hubert
authors.initials: H
authors.lastname: Vaudry
authors.forename: Hyuk Bang
authors.initials: HB
authors.lastname: Kwon
authors.forename: Jae Young
authors.initials: JY
authors.lastname: Seong
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Tsutsui
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D018076:DNA, Complementary / Q000235:genetics; D019143:Evolution, Molecular; D005260:Female; D006801:Humans; D007031:Hypothalamus / Q000378:metabolism; D059648:Kisspeptins; D007798:Lampreys; D008116:Lizards; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009990:Oryzias; D010802:Phylogeny; D010987:Platypus; D020033:Protein Isoforms / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000032:analysis* / Q000235:genetics* / Q000378:metabolism; D000074502:Receptors, Kisspeptin-1; D012754:Sharks; D025521:Tumor Suppressor Proteins / Q000032:analysis* / Q000235:genetics* / Q000378:metabolism; D014714:Vertebrates; D014981:Xenopus; D015027:Zebrafish
chemical_list: D018076:DNA, Complementary; C106628:KISS1 protein, human; C118688:KISS1R protein, human; C491407:Kiss1 protein, mouse; C492248:Kiss1r protein, mouse; D059648:Kisspeptins; D020033:Protein Isoforms; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; D000074502:Receptors, Kisspeptin-1; D025521:Tumor Suppressor Proteins