EXPRESSION CLONING AND PHARMACOLOGICAL CHARACTERIZATION OF A HUMAN HIPPOCAMPAL NEUROPEPTIDE-Y PEPTIDE YY Y2 RECEPTOR SUBTYPE

The pancreatic polypeptide family includes neuropeptide Y (NPY), one o f the most abundant neuropeptides in the mammalian nervous system, as well as peptide YY (PW) and pancreatic polypeptide (PP). This peptide family is involved in numerous physiological processes such as memory, pain, blood pressure, appetite, anxiety, and circadian rhythm. Of the multiple Y-type receptors proposed for PP family members, only the Y1 subtype was cloned previously. We now report the isolation of a human Y2 (hhY2) receptor cDNA by expression cloning from a human hippocampa l cDNA library, using a I-125-PYY binding assay. hhY2 cDNA encodes a p redicted protein of 381 amino acids with low amino acid identity to th e human Y1 receptor (31% overall; 41% transmembrane). I-125-PYY bindin g to transiently expressed hY2 receptors was saturable (pK(d) = 10.17) and displaceable by human PP family members in rank order: PW (pK(i) = 9.47) similar to NPY (pK(i) = 9.27) much greater than PP (pK(i) < 6) and by peptide analogs: NPY2-36 (pK(i) = 8.80) similar to NPY13-36 (p K(i) = 8.55)CB-NPY (pK, = 8.54) > NPY,,,, (pK, = 6.51) [Leu(31),Pro(34 )]Npy (PKi = 6 23). Human PYY decreased [cAMP] and increased intracell ular [Ca2+] in hY2-transfected 293 cells.