Pancreatic polypeptide (PP) is produced in the islets of Langerhans and released in response to meals. It belongs to a family of peptides that also includes neuropeptide Y and peptide YY. In the present communication, we describe a rat receptor with high affinity for PP, therefore named PP1. Clones for the PP1 receptor were obtained by PCR using sequence information for the neuropeptide Y receptor Y1 from several species. The PP1 receptor has 46% overall amino acid sequence identity to the rat Y1 receptor and 56% identity in the transmembrane regions. The PP1 receptor displays a pharmacological profile that is distinct from previously described neuropeptide Y-family receptors. In competition with iodinated bovine PP, it binds rat PP with an affinity (K*) of 0.017 nM, while the affinities for peptide YY and neuropeptide Y are substantially lower with K; values of 162 and 192 nM, respectively. In stably transfected CHO cells, the PP1 receptor inhibits forskolin-stimulated cAMP synthesis. Northern blot hybridizations to a panel of mRNAs detected transcripts in testis and lung. A faint band was seen in colon and total brain. In contrast, the human receptor is expressed primarily in colon and small intestine. Whereas rat and human PP1 bind PP with the same affinity, the rat receptor has much lower affinity than its human ortholog for peptide YY and neuropeptide Y. Interestingly, the amino acid sequence identity between rat and human PP1 is only 75%. Thus, the sequence, the tissue distribution, and the binding profile of the PP1 receptor differ considerably between rat and human.The pancreatic polypeptide (PP)-fold family of neuroendocrine peptides consists of PP, neuropeptide Y (NPY), and peptide YY (PYY). All three peptides have 36 aa and share prominent sequence and three-dimensional structure similarity (1). PP is s.creted from pancreatic islets in response to meals, and it inhibits gall bladder contraction, gut motility, and pancreatic secretion (for review, see ref.2). PP has also been isolated from porcine intestine (3). PYY is found in endocrine cells of the lower intestine (4) as well as in pancreatic islets (5) and a few neuronal populations (6, 7). Its release and actions on the gastrointestinal tract are similar to those of PP (see ref.2). NPY, in contrast, is found in the central and peripheral nervous systems. All three peptides have been found in animal experimentsto increase food intake. NPY is considered to be one of the most potent orexigenic substances known (8), and intracerebroventricular injection of PP stimulates feeding in rats, mice, and dogs (9-12). Anorectic patients have high levels of circulating PP (13,14), whereas obese persons have decreased PP concentrations (15)

No abstract

No abstract

Neuropeptide Y (NPY), peptide YY (PYY), and pancreatic polypeptide (PP) form a family of structurally related peptides. As we have previously isolated clones for NPY and PYY from the zebrafish (Danio rerio), we wished to clone the receptors for these peptides to allow correlation of ligand and receptor distribution. We describe here the cloning and functional expression of a receptor with equally high identity to the NPY-Y1 receptor as to the recently cloned Y4/PP1 and Y6 receptors with an overall amino acid sequence identity of approximately 50%. Furthermore, the zebrafish receptor gene lacks the intron present in the coding region in vertebrate Y1 genes. These features strongly suggest that the zebrafish receptor represents a separate subtype. Hence, we have named it zYb for zebrafish Y-receptor b. (We have also discovered a unique receptor called zYa.) The zYb receptor has a binding profile that is reminiscent of Y1 with affinities for NPY and PYY in the low picomolar range, whereas affinities for Y2-selective ligands are considerably lower. It couples to adenylyl cyclase by inhibiting cAMP synthesis. Receptor mRNA was detected by reverse transcription polymerase chain reaction (RT-PCR) in brain, eye, and intestine. The binding profile and amino acid identity show that the zebrafish zYb receptor is related to Y1 but represents a distinct subtype that is likely to be present also in mammals.

No abstract