Evolution of gonadotropin-inhibitory hormone receptor and its ligand

•GPR147 (NPFFR1) is the receptor for GnIH.•GPR 147 (NPFFR1) and GPR74 (NPFFR2) are paralogs.•GPR147 (NPFFR1), GPR74 (NPFFR2) and SIFR have a common origin.

Gonadotropin-inhibitory hormone (GnIH) is a neuropeptide inhibitor of gonadotropin secretion, which was first identified in the Japanese quail hypothalamus. GnIH peptides share a C-terminal LPXRFamide (X = L or Q) motif in most vertebrates. The receptor for GnIH (GnIHR) is the seven-transmembrane G protein-coupled receptor 147 (GPR147) that inhibits cAMP production. GPR147 is also named neuropeptide FF (NPFF) receptor 1 (NPFFR1), because it also binds NPFF that has a C-terminal PQRFamide motif. To understand the evolutionary history of the GnIH system in the animal kingdom, we searched for receptors structurally similar to GnIHR in the genome of six mammals (human, mouse, rat, cattle, cat, and rabbit), five birds (pigeon, chicken, turkey, budgerigar, and zebra finch), one reptile (green anole), one amphibian (Western clawed flog), six fishes (zebrafish, Nile tilapia, Fugu, coelacanth, spotted gar, and lamprey), one hemichordate (acorn worm), one echinoderm (purple sea urchin), one mollusk (California sea hare), seven insects (pea aphid, African malaria mosquito, honey bee, buff-tailed bumblebee, fruit fly, jewel wasp, and red flour beetle), one cnidarian (hydra), and constructed phylogenetic trees by neighbor joining (NJ) and maximum likelihood (ML) methods. A multiple sequence alignment of the receptors showed highly conserved seven-transmembrane domains as well as disulfide bridge sites between the first and second extracellular loops, including the receptor of hydra. Both NJ and ML analyses grouped the receptors of vertebrates into NPFFR1 and NPFFR2 (GPR74), and the receptors of insects into the receptor for SIFamide peptides that share a C-terminal YRKPPFNGSIFamide motif. Although human, quail and zebrafish GnIHR (NPFFR1) were most structurally similar to SIFamide receptor of fruit fly in the Famide peptide (FMRFamide, neuropeptide F, short neuropeptide F, drosulfakinin, myosuppressin, SIFamide) receptor families, the amino acid sequences and the peptide coding regions of GnIH precursors were most similar to FMRFamide precursor of fruit fly in the precursors of Famide peptide families. Chromosome synteny analysis of the precursor genes of human, quail and zebrafish GnIH and fruit fly Famide peptides further identified conserved synteny in vertebrate GnIH and fruit fly FMRFa precursor genes as well as other Famide peptide precursor genes. These results suggest that GnIH and its receptor pair and SIFamide and its receptor pair may have diverged and co-evolved independently in vertebrates and insects, respectively, from their ancestral Famide peptide and its receptor pair, during diversification and evolution of deuterostomian and protostomian species.