TY - JOUR T1 - Y<sub>4</sub> Receptors Mediate the Inhibitory Responses of Pancreatic Polypeptide in Human and Mouse Colon Mucosa JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 20 LP - 30 DO - 10.1124/jpet.106.106500 VL - 319 IS - 1 AU - Iain R. Tough AU - Nicholas D. Holliday AU - Helen M. Cox Y1 - 2006/10/01 UR - http://jpet.aspetjournals.org/content/319/1/20.abstract N2 - 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 ER -