MOLECULAR EVOLUTION OF GPCRS: 26Rfa/GPR103

Abstract

Neuropeptides possessing the Arg-Phe-NH 2 (RFamide) motif at their C-termini (designated as RFamide peptides) have been characterized in a variety of animals. Among these, neuropeptide 26RFa (also termed QRFP) is the latest member of the RFamide peptide family to be discovered in the hypothalamus of vertebrates. The neuropeptide 26RFa/QRFP is a 26-amino acid residue peptide that was originally identified in the frog brain. It has been shown to exert orexigenic activity in mammals and to be a ligand for the previously identified orphan G protein-coupled receptor, GPR103 (QRFPR). The cDNAs encoding 26RFa/QRFP and QRFPR have now been characterized in representative species of mammals, birds, and fish. Functional studies have shown that, in mammals, the 26RFa/QRFP-QRFPR system may regulate various functions, including food intake, energy homeostasis, bone formation, pituitary hormone secretion, steroidogenesis, nociceptive transmission, and blood pressure. Several biological actions have also been reported in birds and fish. This review summarizes the current state of identification, localization, and understanding of the functions of 26RFaQRFP and its cognate receptor, QRFPR, in vertebrates.

Positive selection effects on the biochemical properties of mammal pyroglutamylated RFamide peptide receptor (QRFPR)

“…In birds, as in mammals, 26RFa/QRFP-producing neurons are located in the hypothalamus, while QRFPR is widely distributed throughout the brain. In birds, 26RFa/ QRFP also exerts an orexigenic action, and a similar effect has been suggested in fish (Ukena et al 2014).…”

“…In contrast to a recent study (Ukena et al 2014) that proposed three ancestral vertebrate QRFPR subtypes, analyses by Larhammar and colleagues (2014) identified four ancestral vertebrate QRFP receptor genes. Furthermore, they proposed a likely scenario for the gene duplications in early vertebrate evolution in relation to the vertebrate tetraploidization, which showed that mammals have lost much of the QRFP system.…”

“…Possibly, this explains why the single QRFP peptide found in mammalian genomes seems to have diverged from other vertebrates, which still retain more extensive QRFP receptor repertoires. However, the structure, distribution pattern and biological actions of the 26RFa/QRFP-QRFPR system have been conserved across the vertebrate phylum, from fish to mammals (Ukena et al 2014). Thus, in order to have further information on the molecular evolution of these proteins in relation to the functional significance of 26RFa/QRFP-QRFPR pair in vertebrates, we verify the presence of natural selection on mammals' qrfpr gene.…”

“…In addition, QRFPR possesses several features characteristic of class A GPCRs, such as: (1) a disulfide bridge between the two Cys residues located in the first and second extracellular loops (EL1 and EL2); (2) the existence of an Asp residue within the second transmembrane domain (TM2), that seems to play a pivotal role in G protein coupling; (3) a conserved Glu-Arg doublet sequence at the N-terminus of the second intracellular loop (IL2); (4) three conserved residues, i.e. Phe, Pro and Asn, within TM6 and TM7, which are crucial for receptor activation (Ukena et al 2014). Previous results suggested that QRFPR is coupled to a Gi/0 and/or to a Gq protein (Fukusumi et al 2003).…”

“…Phylogenetic analysis data are consistent with synteny analysis. Although in the genome database there are homologous sequences of QRFPR in Xenopus, zebrafish, coelacanth and lamprey (Ukena et al 2014), qrfpr has been studied only in mammals and birds.…”