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Volume 271, Number 44, Issue of November 1, 1996 pp. 27217-27220
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.

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Inactivation of a Novel Neuropeptide Y/Peptide YY Receptor Gene in Primate Species

(Received for publication, August 9, 1996)

From the Neuroscience & Gastrointestinal Research Laboratory, ^¶ Molecular Medicine Research Laboratory, Institute for Drug Discovery Research, and the ^§ Clinical Pharmacology Research Laboratory, Institute for Drug Development Research, Yamanouchi Pharmaceutical Co., Ltd., 21 Miyukigaoka, Tsukuba, Ibaraki, 305, Japan

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 [Leu³¹,Pro³⁴]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.

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