MOLECULAR EVOLUTION OF GPCRS: Kisspeptin/kisspeptin receptors

    1. Sylvie Dufour
    1. Laboratory of Biology of Aquatic Organisms and Ecosystems (BOREA) , UMR CNRS 7208, IRD207, Université Pierre and Marie Curie – Paris 6, Muséum National d'Histoire Naturelle, 7 rue Cuvier, CP32, 75231 Paris Cedex 05, France
      1 Laboratory of Neuronal and Neuroendocrine Differentiation and Communication , INSERM U982, Institute for Research and Innovation in Biomedicine (IRIB), University of Rouen, 76821 Mont-Saint-Aignan, France
    1. Correspondence should be addressed to S Dufour; Email: dufour{at}


    Following the discovery of kisspeptin (Kiss) and its receptor (GPR54 or KissR) in mammals, phylogenetic studies revealed up to three Kiss and four KissR paralogous genes in other vertebrates. The multiplicity of Kiss and KissR types in vertebrates probably originated from the two rounds of whole-genome duplication (1R and 2R) that occurred in early vertebrates. This review examines compelling recent advances on molecular diversity and phylogenetic evolution of vertebrate Kiss and KissR. It also addresses, from an evolutionary point of view, the issues of the structure–activity relationships and interaction of Kiss with KissR and of their signaling pathways. Independent gene losses, during vertebrate evolution, have shaped the repertoire of Kiss and KissR in the extant vertebrate species. In particular, there is no conserved combination of a given Kiss type with a KissR type, across vertebrate evolution. The striking conservation of the biologically active ten-amino-acid C-terminal sequence of all vertebrate kisspeptins, probably allowed this evolutionary flexibility of Kiss/KissR pairs. KissR mutations, responsible for hypogonadotropic hypogonadism in humans, mostly occurred at highly conserved amino acid positions among vertebrate KissR. This further highlights the key role of these amino acids in KissR function. In contrast, less conserved KissR regions, notably in the intracellular C-terminal domain, may account for differential intracellular signaling pathways between vertebrate KissR. Cross talk between evolutionary and biomedical studies should contribute to further understanding of the Kiss/KissR structure–activity relationships and biological functions.

    • Revision received 7 February 2014
    • Accepted 25 February 2014
    • Made available online as an Accepted Preprint 27 February 2014
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