The cloned rat pancreatic polypeptide receptor exhibits profound differences to the orthologous receptor.

Abstract

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)

Generation of the Melatonin Endocrine Message in Mammals: A Review of the Complex Regulation of Melatonin Synthesis by Norepinephrine, Peptides, and Other Pineal Transmitters

“…Y n -R were identified (see Larhammar, 1996;Michel et al, 1998 for reviews): Y 3 -R (Herzog et al, 1993), Y 4 -R (Lundell et al, 1996), Y 5 -R (Hu et al, 1996;Haynes et al, 1998, the "food intake" receptor), and Y 6 -R (Weinberg et al, 1996). In addition, it is noteworthy that several studies have suggested that NPY may be one of the endogenous ligands of receptors (Roman et al, 1989).…”

The Peptide YY-Preferring Receptor Mediating Inhibition of Small Intestinal Secretion Is a Peripheral Y2Receptor: Pharmacological Evidence and Molecular Cloning

“…They are heptahelical G protein-coupled receptors and are referred to as Y receptors (Michel et al, 1998). Y 1 , Y 2 , and Y 5 receptors have similar affinity to NPY and PYY, whereas Y 4 receptor seems to be specific for PP (Voisin et al, 2000) although there was initial confusion regarding its pharmacological profile (Bard et al, 1995;Lundell et al, 1995Lundell et al, , 1996Yan et al, 1996). A Y 6 receptor has been cloned in mice (Weinberg et al, 1996) but seems to be absent in rats (Burkhoff et al, 1998).…”

Chicken neuropeptide Y-family receptor Y4: a receptor with equal affinity for pancreatic polypeptide, neuropeptide Y and peptide YY

“…The integrity of Figure 1 Amino acid sequence alignment made using the Lasergene DNASTAR Megalign software. The chY4 receptor serves as master sequence in alignment with human (Lundell et al 1995), guinea pig (Eriksson et al 1998), pig , rat (Lundell et al 1996) and mouse (Gregor et al 1996) Y4 receptors. Dashes represent gaps introduced to optimise alignment.…”

“…In mammals, the affinity of pancreatic polypeptide for this receptor is much greater than the affinities of NPY and PYY (Bard et al 1995, Lundell et al 1995, 1996, Gregor et al 1996. The rat receptor is even more selective for pancreatic polypeptide than are the human and guinea pig receptors (Lundell et al 1996, Eriksson et al 1998. In mammals, the Y4 receptor has a modest neuronal expression in the paraventricular nucleus and in the brainstem (Dumont & Quirion 2000, Larsen & Kristensen 2000, but has a wider peripheral expression in the gut, which agrees well with the role of pancreatic peptide in regulating gastrointestinal functions (Hazelwood 1993, Voisin et al 2000.…”

“…2). Furthermore, from studies in mammals, Y4 is already known to evolve more rapidly (Lundell et al 1996).…”