Y(4) receptors mediate the inhibitory responses of pancreatic polypeptide in human and mouse colon mucosa.
The antisecretory effects of several Y agonists, including pancreatic polypeptide (PP), indicate the presence of Y(1), Y(2), and Y(4) receptors in mouse and human (h) colon mucosae. Here, we used preparations from human and from wild-type (WT), Y(4), and Y(1) receptor knockout ((-/-)) mice, alongside Y(4) receptor-transfected cells to define the relative functional contribution of the Y(4) receptor. First, rat (r) PP antisecretory responses were lost in murine Y(4)(-/-) preparations, but hPP and Pro(34) peptide YY (PYY) costimulated Y(4) and Y(1) receptors in WT mucosa. The Y(1) antagonist/Y(4) agonist GR231118 [(Ile,Glu,Pro,Dpr,Tyr,Arg,Leu,Arg,Try-NH(2))-2-cyclic(2,4'),(2',4)-diamide] elicited small Y(4)-mediated antisecretory responses in human tissues pretreated with the Y(1) antagonist, BIBO3304 [(R)-N-[[4-(aminocarbonylaminomethyl)-phenyl]methyl]-N(2)-(diphenylacetyl)-argininamide trifluoroacetate)], and attenuated Y(4)-mediated hPP responses in mouse and human mucosa. GR231118 and rPP were also antisecretory in hY(4)-transfected epithelial monolayers but were partial agonists compared with hPP at this receptor. In Y(4)-transfected human embryonic kidney (HEK) 293 cells, Y(4) ligands displaced [(125)I]hPP binding with orders of affinity (pK(i)) at human (hPP = rPP > GR231118 > Pro(34)PYY = PYY) and mouse (rPP = hPP > GR231118 > Pro(34)PYY > PYY) Y(4) receptors. GR231118- and rPP-stimulated guanosine 5'-3-O-(thio)triphosphate binding through hY(4) receptors with significantly lower efficacy than hPP. GR231118 marginally increased basal but abolished further PP-induced hY(4) internalization to recycling (transferrin-labeled) pathways in HEK293 cells. Taken together, these findings show that Y(4) 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.
Tough
Iain R
IR
Wolfson Centre for Age-Related Diseases, King's College London, Guy's Campus, London SE1 1UL, UK.
Holliday
Nicholas D
ND
Cox
Helen M
HM
D000595:Amino Acid Sequence; D000818:Animals; D003106:Colon / Q000187:drug effects*; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006801:Humans; D007413:Intestinal Mucosa / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D010191:Pancreatic Polypeptide / Q000494:pharmacology*; D010456:Peptides, Cyclic / Q000494:pharmacology; D051381:Rats; D017476:Receptors, Neuropeptide Y / Q000502:physiology*; D013045:Species Specificity
C097287:1229U91; D010456:Peptides, Cyclic; D017476:Receptors, Neuropeptide Y; D016244:Guanosine 5'-O-(3-Thiotriphosphate); C109491:neuropeptide Y4 receptor; D010191:Pancreatic Polypeptide