GPR50 is the mammalian ortholog of Mel1c: Evidence of rapid evolution in mammals

Abstract

BackgroundThe melatonin receptor subfamily contains three members Mel1a, Mel1b and Mel1c, found in all vertebrates except for Mel1c which is found only in fish, Xenopus species and the chicken. Another receptor, the melatonin related receptor known as GPR50, found exclusively in mammals and later identified as a member of the melatonin receptor subfamily because of its identity to the three melatonin receptors despite its absence of affinity for melatonin. The aim of this study was to describe the evolutionary relationships between GPR50 and the three other members of the melatonin receptor subfamily.ResultsUsing an in silico approach, we demonstrated that GPR50 is the ortholog of the high affinity Mel1c receptor. It was necessary to also study the synteny of this gene to reach this conclusion because classical mathematical models that estimate orthology and build phylogenetic trees were not sufficient. The receptor has been deeply remodelled through evolution by the mutation of numerous amino acids and by the addition of a long C-terminal tail. These alterations have modified its affinity for melatonin and probably affected its interactions with the other two known melatonin receptors MT1 and MT2 that are encoded by Mel1a and Mel1b genes respectively. Evolutionary studies provided evidence that the GPR50 group evolved under different selective pressure as compared to the orthologous groups Me11 a, b, and c.ConclusionThis study demonstrated that there are only three members in the melatonin receptor subfamily with one of them (Me11c) undergoing rapid evolution from fishes and birds to mammals. Further studies are necessary to investigate the physiological roles of this receptor.

International Union of Basic and Clinical Pharmacology. LXXV. Nomenclature, Classification, and Pharmacology of G Protein-Coupled Melatonin Receptors

“…An in silico approach has suggested that GPR50 is the ortholog of the Mel 1C receptor (Dufourny et al, 2008). This conclusion is based on an analysis of the melatonin receptor family phylogenetic tree and the conserved synteny of genes surrounding the Mel 1C and GPR50 genes.…”

A Review of Melatonin, Its Receptors and Drugs

“…MT2 receptors may be the new target for development of hypnotic agents [2]. [31]. Its gene is located on the X chromosome (Xq28) and consists of 618 amino acids [4].…”

Uneven evolutionary rate of the melatonin-related receptor gene (GPR50) in primates

“…Rich Ser and 2 repeats (RA and SVHFK) were also found in the CTD (Figure 2). Dufourny et al (2008) analyzed the CTD by using a bidimensional Hydrophobic Cluster Analysis. They first aligned the repeated heptapeptide and found a heptad in the C-terminal extension of human GPR50.…”

“…GPR50 is a GPCR recently demonstrated to play an important role in adaptive thermogenesis in response to calorie intake (Levoye et al, 2006). Interestingly, a recent phylogenetic study of GPR50 and the melatonin receptors suggested that GPR50 was the mammalian ortholog of Mel1c (Dufourny et al, 2008); however, the receptor has experienced a number of changes throughout its evolution, including the mutation of numerous amino acids and the addition of a long C-terminal domain (CTD).…”