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Cloning and functional expression of a human Y4 subtype receptor for pancreatic polypeptide, neuropeptide Y, and peptide YY.

Bard J.A., Walker M.W., Branchek T.A., Weinshank R.L.

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). 125I-PYY binding to transiently expressed Y4 receptors was saturable (pKd = 9.89) and displaceable by human PP family derivatives: PP (pKi = 10.25) approximately PP2-36 (pKi = 10.06) > PYY (pKi = 9.06) approximately [Leu31,Pro34]NPY (pKi = 8.95) > NPY (pKi = 8.68) > PP13-36 (pKi = 7.13) > PP31-36 (pKi = 6.46) > PP31-36 free acid (pKi < 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.

J. Biol. Chem. 270:26762-26765(1995) [PubMed] [Europe PMC]

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