Functional consequences of neuropeptide Y Y2 receptor knockout and Y2 antagonism in mouse and human colonic tissues

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Abstract
1 Neuropeptide Y (NPY), peptide YY (PYY) and pancreatic polypeptide (PP) differentially activate three Y receptors (Y(1), Y(2) and Y(4)) in mouse and human isolated colon. 2 The aim of this study was to characterise Y(2) receptor-mediated responses in colon mucosa and longitudinal smooth muscle preparations from wild type (Y(2)+/+) and knockout (Y(2)-/-) mice and to compare the former with human mucosal Y agonist responses. Inhibition of mucosal short-circuit current and increases in muscle tone were monitored in colonic tissues from Y(2)+/+ and Y(2)-/- mice+/-Y(1) ((R)-N-[[4-(aminocarbonylaminomethyl)phenyl)methyl]-N(2)-(diphenylacetyl)-argininamide-trifluoroacetate (BIBO3304) or Y(2) (S)-N(2)-[[1-[2-[4-[(R,S)-5,11-dihydro-6(6H)-oxodibenz[b,e]azepin-11-yl]-1-piperazinyl]-2-oxoethyl]cyclopentyl]acetyl]-N-[2-[1,2-dihydro-3,5(4H)-dioxo-1,2-diphenyl-3H-1,2,4-triazol-4-yl]ethyl]-argininamide (BIIE0246) antagonists. 3 Predictably, Y(2)-/- tissues were insensitive to Y(2)-preferred agonist PYY(3-36) (</=100 nM), but unexpectedly Y(4)-preferred PP responses were right-shifted probably as a consequence of elevated circulating PP levels, particularly in male Y(2)-/- mice (Sainsbury et al., 2002). 4 BIBO3304 and BIIE0246 elevated mucosal ion transport, indicating blockade of inhibitory mucosal tone in Y(2)+/+ tissue. While BIBO3304 effects were unchanged, those to BIIE0246 were absent in Y(2)-/- mucosae. Neither antagonist altered muscle tone; however, BIIE0246 blocked NPY and PYY(3-36) increases in Y(2)+/+ basal tone. BIBO3304 abolished residual Y(1)-mediated NPY responses in Y(2)-/- smooth muscle. 5 Tetrodotoxin significantly reduced BIIE0246 and PYY(3-36) effects in Y(2)+/+ mouse and human mucosae, but had no effect upon Y-agonist contractile responses, indicating that Y(2) receptors are located on submucosal, but not myenteric neurones. 6 Tonic activation of submucosal Y(2) receptors by endogenous NPY, PYY or PYY(3-36) could indirectly reduce mucosal ion transport in murine and human colon, while direct activation of Y(2) receptors on longitudinal muscle results in contraction.