Pharmacological characterization of the cloned neuropeptide Y y(6) receptor.
Neuropeptide Y has potent appetite stimulating effects which are mediated by hypothalamic receptors believed to be of the neuropeptide Y Y(1) and/or neuropeptide Y Y(5) subtype. In mice, the neuropeptide Y y(6) receptor is also expressed in the hypothalamus, suggesting that it too may function as a feeding receptor in this species. Several laboratories have studied the pharmacology of the neuropeptide Y y(6) receptor, but their results are not in agreement. Using neuropeptide Y and a variety of peptide analogs and small molecule antagonists, we have determined that the pharmacology of the cloned mouse neuropeptide Y y(6) receptor is distinct from that of the other known neuropeptide Y receptors. The rank order of binding affinity for the mouse neuropeptide Y y(6) receptor is [(Ile, Glu,Pro,Dpr,Tyr,Arg,Leu,Arg,Tyr-NH(2))(2)human peptide YY=human, rat neuropeptide Y=human, rat neuropeptide Y-(2-36)=human, rat [Leu(31), Pro(34)porcine (Cys(2))-neuropeptide Y-(1-4)-8-aminooctanoyl-(D-Cys(27)porcine [D-Trp(32)rat pancreatic polypeptide=human pancreatic polypeptide. A similar rank order of potency is seen for inhibition of forskolin-stimulated cyclic AMP. The neuropeptide Y Y(5) receptor antagonist trans-naphthalene-1-sulfonic acid ¿4-[4-amino-quinazolin-2-ylamino)-methyl]-cyclohexylmethy l¿-amide hydrochloride (CGP 71683A) and the neuropeptide Y Y(1) receptor antagonist ((R)-N(2)-diphenylacetyl)-N-[(4-hydroxyphenyl)methyl]-argininam ide) (BIBP3226) bind weakly to the neuropeptide Y y(6) receptor (K(i)10, 000 nM, respectively). Although the function of the neuropeptide Y y(6) receptor remains to be elucidated, its pharmacology is not consistent with a role in appetite regulation.
Mullins
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Department of Central Nervous System and Cardiovascular Research, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA. deborra.mullins@spcorp.com
Guzzi
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Xia
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Parker
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D000818:Animals; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D006801:Humans; D051379:Mice; D009478:Neuropeptide Y / Q000494:pharmacology*; D010446:Peptide Fragments / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017476:Receptors, Neuropeptide Y / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000187:drug effects / Q000378:metabolism
D009478:Neuropeptide Y; D010446:Peptide Fragments; D017476:Receptors, Neuropeptide Y; D011994:Recombinant Proteins; C109492:neuropeptide Y6 receptor; D000242:Cyclic AMP