Multiple Y receptors mediate pancreatic polypeptide responses in mouse colon mucosa

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

“…However GR231118 per se produced no discernible inhibitory responses in untreated mouse or human colon but conversely increased I sc . Similar increases have been reported in mouse (Cox et al, 2001a;Hyland and Cox, 2005) and human (Cox and Tough, 2002) mucosa following Y 1 antagonists (BIBO3304 and BIBP3226 but not the inactive enantiomer BIBP3435) and are attributed to blockade of endogenous Y 1 inhibitory tone. Y 1 receptor antagonism accordingly converted GR231118-induced increases in I sc to agonist-like decreases in I sc , thus revealing otherwise masked Y 4 activation in human colon.…”

“…1B), but only in Y 1 Ϫ/Ϫ mucosa did it reach a maximum with a pEC 50 of 8.47 Ϯ 0.13, whereas responses in WT and Y 4 Ϫ/Ϫ tissues were linear up to 300 nM. The Y 1 receptor-preferring agonist, Pro 34 PYY (1-300 nM), was significantly more efficacious than rPP or hPP as observed previously (Cox et al, 2001a), and in WT and Y 4 Ϫ/Ϫ mucosae, the pEC 50 values for Pro 34 PYY were 7.53 Ϯ 0.06 and 7.59 Ϯ 0.07 (Fig. 1C) (Fig.…”

“…HEK293T (from Prof. S. J. Hill, University of Nottingham, Nottingham, UK), and HT-29 human adenocarcinoma cells were grown to confluence in DMEM supplemented with 25 mM glucose, 10% fetal bovine serum, 100 g/ml kanamycin, and 1.2 g/ml amphotericin B at 37°C, as described by Holliday et al (2005) Ussing Chamber Studies. Mucosal sheets from mouse and human descending colon were prepared as described previously (Cox et al, 2001a;Cox and Tough, 2002). Preparations with exposed areas of 0.6 (human) or 0.14 (mouse) cm 2 were bathed in oxygenated KH solution at 37°C, and voltage-clamped at 0 mV in an Ussing chamber (DVC1000; WPI, Sarasota, FL).…”

“…Y 1 , Y 2 , and Y 5 receptors are stimulated by PYY or NPY, whereas C-terminal fragments, such as PYY , are Y 2 and Y 5 receptor-preferred agonists. Antisecretory responses to PP, PYY, and NPY in human and mouse colonic mucosa are mediated by a combination of Y 1 , Y 2 , or Y 4 receptors, whereas Y 5 agonists are ineffective (Cox et al, 2001a;Cox and Tough, 2002). Y 1 and Y 4 receptors are expressed by epithelia, whereas Y 2 responses alone are sensitive to the neurotoxin tetrodotoxin, indicating that this receptor is expressed on submucous enteric neurons (Cox and Tough, 2002;Hyland et al, 2003).…”

“…Their subsequent physiological actions include central appetite suppression (Murphy and Bloom, 2004) and peripheral effects on ion transport (Cox and Tough, 2002) and gastrointestinal motility. In ileostomy patients, PYY inhibits vasoactive intestinal polypeptide (VIP)-mediated fluid secretion (Playford et al, 1990), and in vitro NPY, PYY,, and PP inhibit anion secretion in mouse and human colonic mucosa (Cox et al, 2001a;Cox and Tough, 2002). In addition, PYY is responsible for the "ileal brake" that slows gastrointestinal transit to facilitate digestion, thus highlighting the potential for Y-based agonists as natural antidiarrheal agents.…”