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). 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.
Bard
J A
JA
Synaptic Pharmaceutical Corporation, Paramus, New Jersey 07652, USA.
Walker
M W
MW
Branchek
T A
TA
Weinshank
R L
RL
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D003001:Cloning, Molecular; D017931:DNA Primers / Q000235:genetics; D005260:Female; D015870:Gene Expression; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009478:Neuropeptide Y / Q000378:metabolism; D010191:Pancreatic Polypeptide / Q000378:metabolism; D019894:Peptide YY; D010455:Peptides / Q000378:metabolism; D051381:Rats; D011964:Receptors, Gastrointestinal Hormone / Q000145:classification / Q000235:genetics* / Q000378:metabolism; D017476:Receptors, Neuropeptide Y / Q000145:classification / Q000235:genetics* / Q000378:metabolism; D017386:Sequence Homology, Amino Acid
D017931:DNA Primers; D009478:Neuropeptide Y; D010455:Peptides; D011964:Receptors, Gastrointestinal Hormone; D017476:Receptors, Neuropeptide Y; C082172:peptide YY receptor; C029438:receptors, pancreatic polypeptide-specific; D019894:Peptide YY; D010191:Pancreatic Polypeptide