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GPR119 agonist PSN632408 inhibits anion secretion via a pathway involving Y1 receptors in the mouse descending colon GPR119 is a G protein-coupled receptor expressed in the gastrointestinal tract, activated by fatty acid ethanolamides e.g. oleoylethanolamide (OEA) and small-molecule agonists, e.g. PSN632408 (Overton et al., 2006). GPR119 activation results in glucagon-like peptide (GLP) 1 and 2 release from endocrine L-cells (Lauffer et al., 2009) that also contain peptide YY (PYY). The latter inhibits epithelial anion secretion predominantly via Y1 receptors (Cox et al., 2001). OEA also activates PPARα (Fu et al., 2003). Here we investigated the effects of PSN632408 and the putative roles of PPARα, GLP-1 and PYY on ion transport across descending colon mucosal sheets (from male mice, >10 wks, C57BL/6-129/SvJ background), mounted in Ussing chambers and short-circuit current (Isc) recorded (Cox et al., 2001). Mucosae were prestimulated with basolateral (bl) vasoactive intestinal polypeptide (VIP, 10nM). Responses to single apical (ap) additions of PSN632408 (300nM-30μM) reduced Isc with a pEC50 of 5.2 ± 0.2 (maximal response of -21.6 ± 3.4μA.cm-2; n = 11). The PPARα agonist, GW7647 (1μM; ap/bl) had no effect on Isc and PSN632408 (10μM) responses were unaffected by the PPARα antagonist, GW6471 (10μM; ap/bl). The GLP-1 agonist, exendin 4 (100nM; bl) raised Isc (4.4 ± 1.2 μA.cm-2; n = 10), which was attenuated 81.9 ± 18.1% (n = 5) by the GLP-1 receptor antagonist, exendin 9-39 (1μM; bl), unlike PSN632408 (10μM) which was unaffected. In contrast, PSN632408 (10μM) responses were 81.7 ± 11.6% (n = 4) inhibited by the Y1 receptor antagonist, BIBO3304 (300nM; bl; P<0.01). In conclusion these data indicate that in the mouse colon mucosa, PSN632408 (and OEA) stimulates apical GPR119, resulting in PYY release and subsequent paracrine activation of epithelial Y1 receptors causing anti-secretory effects.
Cox et al., (2001) Peptides, 22, 445-52. Supported by the Wellcome Trust.
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