MOLECULAR-BIOLOGY AND PHARMACOLOGY OF MULTIPLE NPY Y-5 RECEPTOR SPECIES HOMOLOGS

NPY is a 36-amino acid peptide which exerts its physiological effects through the activation of a family of G-protein coupled receptors. In vivo and in vitro characterization of the recently cloned rat Y-5 rece ptor suggests that it is a primary mediator of NPY-induced feeding (Ge rald et al., Nature 1996;382:168-171). We now report the molecular clo ning and pharmacological characterization of the human, dog and mouse homologs of the Y-5 receptor. With the exception of a 21 amino acid re peat in the amino terminus of the mouse Y-5 receptor, the sequence of the four species homologs appear to be highly conserved, with 88% to 9 7% amino acid identities between any two species. Similarly, the pharm acological profiles of the four species homologs as determined in porc ine I-125-PYY binding assays show a great deal of conservation, with t he following rank order of affinity: human or porcine NPY, PYY, [Leu(3 1),Pro(34)]NPY, NPY2-36, human PP>human [D-Trp(32)]NPY > rat PP, C2-NP Y. Northern blot analysis reveals that the Y-5 receptor is widely dist ributed in the human brain, with the strongest signals detected in the cortex, putamen and caudate nucleus. The chromosomal localization of the human Y-5 receptor, previously shown to be overlapping and in the opposite orientation to the Y-1 receptor, is determined to be 4q31, th e same locus as previously demonstrated for the human Y-1 receptor (He rzog et al., J Biol Chem 1993;268:6703-6707), suggesting that these re ceptors may be coregulated. These Y-5 species homologs along with corr esponding animal models may be useful in the search for novel therapeu tics in the treatment of obesity and related feeding disorders. (C) 19 98 Elsevier Science B.V. All rights reserved.