CLONING AND FUNCTIONAL EXPRESSION OF A HUMAN Y4 SUBTYPE RECEPTOR FOR PANCREATIC-POLYPEPTIDE, NEUROPEPTIDE-Y, AND PEPTIDE YY

The pancreatic polypeptide family includes pancreatic polypeptide (PP), neuropeptide Y (NPY), and peptide YY (PYY). Members of the PP family regulate numerous physiological processes, including appetite, gastrointestinal transit, anxiety, and blood pressure. Of the multiple Y-type receptors proposed for PP family members, only the Y1 subtype has been cloned previously. We now report the cloning of an additional Y-type receptor, designated Y4, by homology screening of a human placental genomic library with transmembrane (TM) probes derived from the rat Y1 gene. The Y4 genomic clone encodes a predicted protein of 375 amino acids that is most homologous to Y1 receptors from human, rat, and mouse (42% overall; 55% in TM). I-125-PYY binding to transiently expressed Y4 receptors was saturable (pK(d) = 9.89) and displaceable by human PP family derivatives: PP (pK(i) = 10.25) similar to PP2-36 (pK(i) = 10.06) > PYY (pK(i) = 9.06) similar to [Leu(31),pro(34)]NPY (pK(i) = 8.95) > NPY (PKi = 8.68) > PP13-36 (pK(i) = 7.13) > PP31-36 (pK(i) = 6.46) > PP31-36 free acid (pK(i) < 5). Human PP decreased [cAMP] and increased intracellular [Ca2+] in Y4-transfected LMTK(-) cells, Y4 mRNA was detected by reverse transcriptase-polymerase chain reaction in human brain, coronary artery, and ileum, suggesting potential roles for Y4 receptors in central nervous system, cardiovascular, and gastrointestinal function.