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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Y₄ Receptors Mediate the Inhibitory Responses of Pancreatic Polypeptide in Human and Mouse Colon Mucosa

Wolfson Centre for Age-Related Diseases, King's College London, London, United Kingdom

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 (pK_i) at human (hPP = rPP > GR231118 > Pro³⁴PYY = PYY) and mouse (rPP = hPP > GR231118 > Pro³⁴PYY > 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.

Address correspondence to: Dr. Helen M. Cox, Wolfson Centre for Age-Related Diseases, King's College London, Guy's Campus, London SE1 1UL, UK. E-mail: helen.m.cox{at}kcl.ac.uk

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