PT - JOURNAL ARTICLE AU - Iain R. Tough AU - Nicholas D. Holliday AU - Helen M. Cox TI - Y<sub>4</sub> Receptors Mediate the Inhibitory Responses of Pancreatic Polypeptide in Human and Mouse Colon Mucosa AID - 10.1124/jpet.106.106500 DP - 2006 Oct 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 20--30 VI - 319 IP - 1 4099 - http://jpet.aspetjournals.org/content/319/1/20.short 4100 - http://jpet.aspetjournals.org/content/319/1/20.full SO - J Pharmacol Exp Ther2006 Oct 01; 319 AB - The antisecretory effects of several Y agonists, including pancreatic polypeptide (PP), indicate the presence of Y1, Y2, and Y4 receptors in mouse and human (h) colon mucosae. Here, we used preparations from human and from wild-type (WT), Y4, and Y1 receptor knockout (-/-) mice, alongside Y4 receptor-transfected cells to define the relative functional contribution of the Y4 receptor. First, rat (r) PP antisecretory responses were lost in murine Y4-/- preparations, but hPP and Pro34 peptide YY (PYY) costimulated Y4 and Y1 receptors in WT mucosa. The Y1 antagonist/Y4 agonist GR231118 [(Ile,Glu,Pro,Dpr,Tyr,Arg,Leu,Arg,Try-NH2)-2-cyclic(2,4′),(2′,4)-diamide] elicited small Y4-mediated antisecretory responses in human tissues pretreated with the Y1 antagonist, BIBO3304 [(R)-N-[[4-(aminocarbonylaminomethyl)-phenyl]methyl]-N2-(diphenylacetyl)-argininamide trifluoroacetate)], and attenuated Y4-mediated hPP responses in mouse and human mucosa. GR231118 and rPP were also antisecretory in hY4-transfected epithelial monolayers but were partial agonists compared with hPP at this receptor. In Y4-transfected human embryonic kidney (HEK) 293 cells, Y4 ligands displaced [125I]hPP binding with orders of affinity (pKi) at human (hPP = rPP &gt; GR231118 &gt; Pro34PYY = PYY) and mouse (rPP = hPP &gt; GR231118 &gt; Pro34PYY &gt; PYY) Y4 receptors. GR231118- and rPP-stimulated guanosine 5′-3-O-(thio)triphosphate binding through hY4 receptors with significantly lower efficacy than hPP. GR231118 marginally increased basal but abolished further PP-induced hY4 internalization to recycling (transferrin-labeled) pathways in HEK293 cells. Taken together, these findings show that Y4 receptors play a definitive role in attenuating colonic anion transport and may be useful targets for novel antidiarrheal agents due to their limited peripheral expression. The American Society for Pharmacology and Experimental Therapeutics