Molecular evolution of NPY receptor subtypes

Abstract

The neuropeptide Y (NPY) system consists in mammals of three peptides and 4-5 G-protein-coupled receptors called Y receptors that are involved in a variety of physiological functions such as appetite regulation, circadian rhythm and anxiety. Both the receptor family and the peptide family display unexpected evolutionary complexity and flexibility as shown by information from different classes of vertebrates. The vertebrate ancestor most likely had a single peptide gene and three Y receptor genes, the progenitors of the Y1, Y2 and Y5 subfamilies. The receptor genes were probably located in the same chromosomal segment. Additional gene copies arose through the chromosome quadruplication that took place before the emergence of jawed vertebrates (gnathostomes) whereupon differential losses of the gene copies ensued. The inferred ancestral gnathostome gene repertoire most likely consisted of two peptide genes, NPY and PYY, and no less than seven Y receptor genes: four Y1-like (Y1, Y4/a, Y6, and Yb), two Y2-like (Y2 and Y7), and a single Y5 gene. Whereas additional peptide genes have arisen in various lineages, the most common trend among the Y receptor genes has been further losses. Mammals have lost Yb and Y7 (the latter still exists in frogs) and Y6 is a pseudogene in several mammalian species but appears to be still functional in some. One challenge is to find out if mammals have been deprived of any functions through these gene losses. Teleost fishes like zebrafish and pufferfish, on the other hand, have lost the two major appetite-stimulating receptors Y1 and Y5. Nevertheless, teleost fishes seem to respond to NPY with increased feeding why some other subtype probably mediates this effect. Another challenge is to deduce how Y2 and Y4 came to evolve an inhibitory effect on appetite. Changes in anatomical distribution of receptor expression may have played an important part in such functional switching along with changes in receptor structures and ligand preferences.