Molecular biology and pharmacology of multiple NPY Y5 receptor species homologs

Abstract 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 receptor suggests that it is a primary mediator of NPY-induced feeding (Gerald et al., Nature 1996;382:168–171). We now report the molecular cloning and pharmacological characterization of the human, dog and mouse homologs of the Y 5 receptor. With the exception of a 21 amino acid repeat 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 97% amino acid identities between any two species. Similarly, the pharmacological profiles of the four species homologs as determined in porcine 125 I-PYY binding assays show a great deal of conservation, with the following rank order of affinity: human or porcine NPY, PYY, [Leu 31 ,Pro 34 ]NPY, NPY 2–36 , human PP>human [ d -Trp 32 ]NPY>rat PP, C2-NPY. Northern blot analysis reveals that the Y 5 receptor is widely distributed 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, the same locus as previously demonstrated for the human Y 1 receptor (Herzog et al., J Biol Chem 1993;268:6703–6707), suggesting that these receptors may be coregulated. These Y 5 species homologs along with corresponding animal models may be useful in the search for novel therapeutics in the treatment of obesity and related feeding disorders.