Molecular characterization of a second mouse pancreatic polypeptide receptor and its inactivated human homologue.
The family of mammalian neuropeptide Y (NPY)/peptide YY (PYY)/pancreatic polypeptide (PP) receptors comprises several G protein-coupled receptors, i.e. Y1, Y2, and Y4/PP1. We now report cloning of a novel member of this family named PP2. The coding region of the mouse PP2 gene reveals no introns and predicts a seven transmembrane domain (TM) receptor of 371 amino acids. Percent identities of the mouse PP2 to mouse Y1, mouse Y4/PP1 and human Y2 receptors are 53, 42, and 31, respectively. The mouse PP2 receptor expressed in COS cells binds rat 125I-PP with high affinity, i.e. IC50 = 65 pM. Pharmacological characterization of 125I-PP binding shows a rank order of potency of PP >> PYY >/= NPY, which is similar to that of the mouse Y4/PP1 receptor. Mouse PP2 transcripts were not detectable by Northern analysis in adult tissues and in 11-, 15-, and 17-day-old embryos. However, a 9.8-kb PP2 transcript was detectable in 7-day-old mouse embryo, i.e. prior to the organogenesis of pancreas and the onset of PP production. We have also cloned the human homologue of PP2, which is a single copy gene and maps to human chromosome 5q31. Surprisingly, the human PP2 cDNAs and gene sequences display a single base deletion in the coding region. This frameshifting mutation predicts a truncated receptor of 290 amino acids without TM7. Transfection of COS-7 cells with several different human PP2 expression constructs failed to confirm any specific binding of 125I-PP, 125I-PYY, or 125I-NPY to cell membranes. These data suggest that in mouse there are at least two PP receptors, Y4/PP1 and PP2, whereas in humans, PP2 is either functionally inactive or it has acquired a PP-independent function.
Metabolic Disorders Research, Bayer Corporation, West Haven, Connecticut 06516, USA. Gregor@wh.bayer.com
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Gregor
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Feng
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DeCarr
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Cornfield
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McCaleb
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D019556:COS Cells; D002874:Chromosome Mapping; D002895:Chromosomes, Human, Pair 5; D003001:Cloning, Molecular; D017931:DNA Primers; D005314:Embryonic and Fetal Development; D005260:Female; D016368:Frameshift Mutation; D018507:Gene Expression Regulation, Developmental; D005865:Gestational Age; D006801:Humans; D007438:Introns; D008297:Male; D008322:Mammals; D051379:Mice; D008969:Molecular Sequence Data; D009928:Organ Specificity; D010191:Pancreatic Polypeptide / Q000378:metabolism; D016133:Polymerase Chain Reaction; D051381:Rats; D011964:Receptors, Gastrointestinal Hormone / Q000096:biosynthesis* / Q000737:chemistry / Q000235:genetics*; D017476:Receptors, Neuropeptide Y / Q000737:chemistry / Q000235:genetics; D017386:Sequence Homology, Amino Acid; D012689:Sequence Homology, Nucleic Acid
D017931:DNA Primers; C102315:Npy6r protein, mouse; D011964:Receptors, Gastrointestinal Hormone; D017476:Receptors, Neuropeptide Y; C029438:receptors, pancreatic polypeptide-specific; D010191:Pancreatic Polypeptide