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Neuropeptide Y (NPY), peptide YY (PYY), and pancreatic polypeptide (PP) belong to a family of structurally related peptides which have numerous functions in both neural and endocrine signaling. By homology screening, we cloned a novel gene sharing the highest homology with the NPY Y1 receptor gene from humans, rabbits, and several other species. This novel gene of rabbit encodes a functional NPY/PYY receptor, designated Y2b, which prefers NPY 13-36 rather than [Leu 31 ,Pro 34 ]NPY despite its higher identity with the Y1 receptor. Although, at low levels, mRNA was detected in the tissues and brain regions, including hypothalamus. Further, sequence data revealed that this gene is the orthologue of the recently cloned mouse novel NPY receptor, Y5. However, our study demonstrates that the receptor function of this gene has been inactivated in primates by a frameshift mutation occurring early in primate evolution. This novel NPY receptor represents the first neurotransmitter receptor identified that has universally lost its receptor function in primate species. Interestingly, despite its inactivation in humans, the transcripts were abundantly detected in the heart and skeletal muscle, suggesting a novel function of the human gene.Neuropeptide Y (NPY), 1 peptide YY (PYY), and pancreatic polypeptide (PP) belong to a family of structurally related 36-amino acid peptides which have functions in both neural and endocrine signaling. These peptides exert their actions via receptors on the targeted neurons and peripheral cells. Several receptor subtypes have been defined by their ability to bind NPY, PYY, PP, and derivatives of these peptides. Earlier studies classified this receptor family into at least three receptor subtypes, Y1, Y2, and Y3 (1). The existence of additional receptors were also proposed, "atypical" Y1 receptor (mediating the feeding response of NPY in hypothalamus), PP-preferring receptor (exerting PP activity), and PYY-preferring receptor (2, 3). Molecular cloning studies have revealed the structure of Y1, Y2, and Y4/PP1 receptors (4 -9). These are all heptahelix (seven-transmembrane regions) receptors which couple to G-proteins. The Y4/PP1 receptor has higher affinity for PP than PYY and NPY, suggesting this receptor to be a member of PP receptors.As yet unknown members of this NPY receptor family are expected to be identified by molecular cloning. Very recently, during the course of the present work, the cloning and characterization of mouse Y5 (10) and rat Y5 (11) receptors was reported. The mouse Y5 receptor has significant homology with the Y1 receptor, but the rat Y5 receptor has little identity with the previously cloned NPY receptors, showing that these receptors are not species orthologues, despite having the same name, Y5. In the present report, we describe the cloning of a novel gene sharing the highest homology with the Y1 receptor from humans, rabbits, and several other species. Our study revealed that this novel gene is the orthologue of the mouse Y5 receptor gene (10) and encodes functional ...

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This study was designed to investigate the effects of endomorphin 1 and 2, recently identified mu-opioid receptor selective peptides, on food intake and anxiety in non-food-deprived mice. The intracerebroventricular (i.c.v.) injection of either endomorphin 1 or 2 (0.03-30 nmol) increased food intake in a dose-related manner. A significant increase was observed 20 min after i.c.v. injection of endomorphin 1 or 2 and continued for 4 h. In the elevated plus maze test, the i.c.v. injection of endomorphin 1 (30 nmol) significantly decreased the normal preference for the closed arms. These results suggest that endomorphin produces orexigenic and anxiolytic effects, and that the mu-opioid receptor contributes to the regulation of feeding and anxiety in mice.