KissWiki Basic Biology Discovery of GPR 54 (Kisspeptin Receptor)
Kisspeptins are the natural ligands for the orphan GPCR known as gpr-54 in rat (Lee et al., 1999) and AXOR12 in humans (Muir et al., 2001). However, for ease, throughout the rest of this Wiki only gpr-54 (or its newer name kiss -1R) designation will be used. Gpr-54 is a 396 amino acid receptor and is a member of the rhodopsin family/Class A g-protein coupled receptors.
Gpr-54 was first discovered in 1999 by a PCR search of rat brain, as an orphan receptor related to galanin receptors (GalR). Gpr-54 had a 45% homology to GalR1-3; however had a relatively low affinity for the ligand, galanin (Lee et al., 1999). Then in 2001, two papers reported that peptides derived from the KiSS-1 gene (kisspeptins) were the natural ligands for gpr-54 (Kotani et al., 2001; Muir et al., 2001). Muir et al. used a reverse pharmacology system, screening a large library of possible ligands for calcium mobilization (Muir et al., 2001). Whereas, Kotani et al. purified fractions from tissue extracts where gpr-54 was known to be expressed. These were then tested on an aequorin-based luminescence assay and two hplc peaks from the placental extract where purified and sequenced. The sequence and mass was then compared to protein and nucleotide sequence libraries to identify kisspeptin-13 and kisspeptin-10 (Kotani et al., 2001). These studies also discovered, that gpr-54 is highly conserved among mammals with the human receptor having 85% homology to the rat receptor, 80% homology to the mouse (Clements et al., 2001) and about 40% homology to non-mammalian vertebrates, such as bullfrogs (Moon et al., 2008).
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