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Volume 271, Number 44, Issue of November 1, 1996 pp. 27776-27781
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.

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Molecular Characterization of a Second Mouse Pancreatic Polypeptide Receptor and Its Inactivated Human Homologue

(Received for publication, June 28, 1996)

From the Metabolic Disorders Research, Bayer Corporation, West Haven, Connecticut 06516

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.

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