INACTIVATION OF A NOVEL NEUROPEPTIDE-Y PEPTIDE YY RECEPTOR GENE IN PRIMATE SPECIES

Neuropeptide Y (NPY), peptide YY (PYY), and pancreatic polypeptide (PP ) belong to a family of structurally related peptides which have numer ous functions in both neural and endocrine signaling, By homology scre ening, we cloned a novel gene sharing the highest homology with the NP Y Y1 receptor gene from humans, rabbits, and several other species. Th is novel gene of rabbit encodes a functional NPY/PYY receptor, designa ted Y2b, which prefers NPY13-36 rather than [Leu(31,)Pro(34)]NPY despi te its higher identity with the Y1 receptor. Although, at low levels, mRNA was detected in the tissues and brain regions, including hypothal amus. Further, sequence data revealed that this gene is the orthologue of the recently cloned mouse novel NPY receptor, Y5. However, our stu dy demonstrates that the receptor function of this gene has been inact ivated in primates by a frameshift mutation occurring early in primate evolution. This novel NPY receptor represents the first neuro transmi tter receptor identified that has universally lost its receptor functi on in primate species. Interestingly, despite its inactivation in huma ns, the transcripts were abundantly detected in the heart and skeletal muscle, suggesting a novel function of the human gene.