Structure, Synthesis, and Phylogeny of Kisspeptin and its Receptor - Kisspeptin Signaling in Reproductive Biology - page 8

Introduction
As introduced in Chap. 1 , kisspeptin is now considered to be an essential component
of the central regulation of reproduction, because the lack of Kiss1 or kisspeptin
receptor ( Kiss1r or Gpr54 ) genes causes hypogonadotropic hypogonadism in
humans and rodents. On the other hand, accumulating evidence suggests that kiss2 ,
a paralogous gene for kiss1 , widely exists in the vast majority of vertebrates,
although this gene appears to have been lost in placental mammals. Because the
peptide products of these paralogous genes, Kiss1 and Kiss2, 1 show the same extent
of receptor activation for Gpr54, these genes, which probably have arisen by
genome-wide duplication, should be considered as “kisspeptins” from both receptor
affi nity and phylogenetic viewpoints.
In this chapter, we will introduce the structure and phylogeny of kisspeptin pep-
tides fi rst. Then, projections and steroid sensitivity of the kisspeptin-expressing
neurons will be discussed. Finally, because it is known that kisspeptins, Kiss1 and
Kiss2, belong to the RFamide family, we also discuss the characteristics of kiss-
peptins as members of the RFamide family peptides.
Structure of Kisspeptin
Like other peptide neurotransmitters/neuromodulators, kisspeptin is initially trans-
lated into long kisspeptin precursors, which are cleaved or processed to form shorter
mature peptides. For instance, the human kisspeptin is fi rst translated to prepro-
kisspeptin (Kisspeptin-145, consisting of 145 amino acids), including the signal
peptide to be loaded to the peptide vesicles. The peptide is then proteolytically
cleaved at the site next to the dibasic residues by subtilisin-like convertase, and the
C terminal-RFG is amidated by carboxypeptidase, as in the processing of GnRH
peptides [ 1 ]. Because several other kisspeptin peptides shorter than 54 amino acid
residues have also been found, it is suggested that the peptides are degraded from
the N terminus to produce shorter but still active peptides (Fig. 2.1a ). From human
placental extracts, for example, kisspeptin-54, -14, and -13 have been purifi ed [ 1 , 2 ].
Although the relative potency for their activation of the receptor Gpr54 varies
slightly when the N terminal amino acid length changes, it was suggested that 10
amino acid residues from the C terminal RY-NH 2 (for instance, YNWNSFGLRY-NH 2
for rodent Kiss1 , and YNWNSFGLRF-NH 2 for primates; see Fig. 2.1b ) are essen-
tial and suffi cient for the activation of Gpr54 signaling pathways. For Kiss2, a kiss-
peptin-12 isoform (SKFNFNPFGLRF-NH 2 ) has been isolated from Xenopus laevis
1 According to the Zebrafi sh Information Network, ZFIN; http://zfi n.org/zfi nfo/nomen.html , we
will italicize gene names, such as kiss1 and kiss2 , and romanize protein and peptide name, such as
Kiss1 and Kiss2 in this chapter. We will call the receptor for kisspeptins as “GPR54” because of
the promiscuous nature of ligands and receptors for RF amide families, including kisspeptin. For
details, see Kanda and Oka [ 37 ].