Structural diversity of receptors for neuropeptide Y, peptide YY and pancreatic polypeptide

The NPY (neuropeptide Y) family of neuroendocrine peptides consists of NPY, PYY (peptide YY) and PP (pancreatic polypeptide). Several receptors have been characterized pharmacologically of which three have now been cloned. All three belong to the superfamily of receptors that couple to G proteins and all three cause inhibition of cAMP accumulation. Receptor subtypes Y1 and Y2 bind both NPY and PYY. Surprisingly, Y1 and Y2 share only 31% overall sequence identity, the lowest percentage reported for receptors that bind the same peptide ligand. Nevertheless, each subtype is 94% identical between human and rat, suggesting a slow rate of change. These observations suggest that Y1 and Y2 started to diverge from one another very long ago, possibly before the origin of vertebrates. The PP receptor, called PP1 or Y4, is 42% identical to the Y1 receptor (57% in the transmembrane regions) and is one of the most rapidly evolving receptors with only 75% overall identity between man and rat. Interestingly, this receptor's preferred ligand, PP, also evolves extremely rapidly. The PP receptor also differs between man and rat in tissue distribution and binding properties. The Y1 and PP receptors bind to both termini of their ligands whereas Y2 mainly interacts with the C-terminal part. Thus, within the same family there are highly conserved receptors and peptide ligands as well as one rapidly evolving receptor and ligand.