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RFamide peptide in animals goes back to the fi nding of FMRFamide in sunray
Venus clam Macrocallista nimbosa [ 64 ]. Many RFamides have been identifi ed in
invertebrates since then [ 65 ], although their evolutionary relationship to the verte-
brate RFamide family is yet to be elucidated. Among the vertebrate RFamide fam-
ily, it is suggested that kiss1 , kiss2 , rfrp / gnih , and npff / pqrf had already diverged in
the basal vertebrate, because these four genes have been identifi ed in lamprey
[ 3 , 66 - 68 ]. Like the paralogous relationship of kiss1 and kiss2 , rfrp and npff are also
considered to be duplicated during the whole genome duplication, because they are
closely located to the HoxA and HoxC cluster respectively, which are supposed to
be duplicated in the whole genome duplication [ 69 ]. On the other hand, prrp and
qrfp ( 26rf ) have been identifi ed only in teleosts and tetrapods so far, and the pres-
ence of these genes in the ancestral vertebrate is still argued. Thus, including kiss1
and kiss2 , the RFamide family has already been listed in the early evolution of ver-
tebrate lineage.
It is important to note that their receptors are also close to one another both in
sequence and binding capacity for the relative ligands. In fact, human Kiss1 is
shown to activate Gpr74 and Gpr147 [ 70 , 71 ], suggesting the promiscuous relation-
ship between the ligand and receptor among the RFamide group. Interestingly, in
spite of this promiscuous relationship, the properties of the receptors are completely
different; Gpr54 couples to Gq [ 2 ], whereas Gpr147 and Gpr74 both couple to Gi
and Gs [ 72 ]. In fact, in contrast to kisspeptin, RFRP has been shown to inhibit repro-
duction [ 73 - 79 ]. Thus, the effect of in vivo or in vitro administration of peptides
should be considered with caution, because of the pharmacological side effects via
different types of receptors. In the central nervous system, the precise information
on the projection of each neuron makes it possible to discriminate the promiscuous
ligand-receptor relationship of RFamide and their receptor family.
Conclusions
In this chapter, the structure, function, and phylogeny of kisspeptin and Gpr54, and
projection and steroid sensitivity of kisspeptin neurons were discussed. It is a com-
plex but interesting situation that the RFamide family of peptides show promiscu-
ous ligand-receptor relationships, thereby making the results of in vivo
pharmacological experiments not always possible to tell the natural or physiological
effects of RFamides in the central nervous system. Comprehensive understanding of
the morphological/anatomical and physiological characteristics of the neurons,
receptor distributions, and ontogenic expression may explain the kisspeptin func-
tions at the organismal level and the mechanisms of kisspeptin actions in the brain.
Moreover, the kiss1 and kiss2 genes, and the neurons expressing these genes, may
be considered as the model for the study of paralogous gene functions, because the
genes have avoided strong selection pressure in vertebrates other than mammals,
unlike the GnRH system. Consequently, studies of kisspeptin may open a new era
of understanding the physiological functions of paralogous genes in addition to a
better understanding of neuroendocrine systems.
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