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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on June 28, 2006; DOI: 10.1124/jpet.106.106500

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Received for publication April 20, 2006.
Revised June 14, 2006.
Accepted for publication June 27, 2006.

Y4 RECEPTORS MEDIATE THE INHIBITORY RESPONSES OF PANCREATIC POLYPEPTIDE IN HUMAN AND MOUSE COLON MUCOSA

Iain R Tough 1, Nicholas D Holliday 1, Helen M Cox 1*

1 KCL Wolfson Centre for Age Related Diseases

* Address correspondence to: E-mail: helen.m.cox{at}kcl.ac.uk

Abstract

The antisecretory effects of several Y agonists, including pancreatic polypeptide (PP), indicate the presence of Y1, Y2 and Y4 receptors in mouse (m) and human (h) colon mucosae. Here we used preparations from human, and from wild type, 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 Pro34PYY co-stimulated Y4 and Y1 receptors. The Y1 antagonist/Y4 agonist, GR231118 elicited small Y4-mediated antisecretory responses in human tissues pretreated with BIBO3304, 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 when compared to hPP at this receptor. In transfected HEK293 cells, Y4 ligands displaced [125I]hPP binding with orders of affinity (pKi); at human (hPP = rPP > GR231118 > Pro34PYY = PYY) and mouse (rPP = hPP > GR231118 > Pro34PYY > PYY) Y4 receptors. GR231118 and rPP stimulated GTP{gamma}[35S] binding through hY4 receptors with significantly lower efficacy than hPP. GR231118 marginally increased basal, but abolished further PP-induced hY4 internalization to recycling (transferrin-labelled) 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.


Key words: Colon mucosa, Epithelial ion transport, G-protein efficacy, Pancreatic polypeptide, Y receptor pharmacology, Y4 receptors


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