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Vol. 295, Issue 1, 410-416, October 2000

Intestinal Type 2 Proteinase-Activated Receptors: Expression in Opioid-Sensitive Secretomotor Neural Circuits That Mediate Epithelial Ion Transport1

Benedict T. Green, Nigel W. Bunnett, Anjali Kulkarni-Narla, Martin Steinhoff and David R. Brown

Department of Veterinary PathoBiology, College of Veterinary Medicine, University of Minnesota, St. Paul, Minnesota (B.T.G., A.K-N., D.R.B.); and Departments of Physiology and Surgery, School of Medicine, University of California, San Francisco, California (N.W.B., M.S.)

Trypsin and mast cell tryptase cleave within the extracellular N terminus of proteinase-activated receptor-2 (PAR-2), exposing a tethered ligand (SLIGRL) that binds and activates the cleaved receptor. We examined the neuronal expression of PAR-2 and its role in intestinal ion transport. Short-circuit current elevations in response to trypsin or the receptor-activating peptide SLIGRL-NH2 were measured in sheets of mucosa-submucosa from porcine ileum. SLIGRL-NH2 or trypsin rapidly elevated short-circuit current after their contraluminal application with respective 50% effective concentrations of 184 and 769 nM. Their actions were attenuated after contraluminal administration of the neuronal conduction blocker saxitoxin (0.1 µM); the cyclooxygenase inhibitor indomethacin (10 µM); or the Na+/K+/Cl- cotransport inhibitor furosemide (10 µM), but not by atropine (0.1 µM), a muscarinic cholinergic antagonist. In addition, soybean trypsin inhibitor (5 µg/ml) reduced mucosal responses to trypsin. The delta -opioid agonist [D-Pen2,5]-enkephalin (0.1 µM) inhibited trypsin action, an effect that was prevented by naltrindole (0.1 µM), a delta -opioid antagonist. PAR-2 immunofluorescence was localized in the mucosa using a receptor-specific antibody. PAR-2-like immunoreactivity was detected in myenteric and submucosal neurons, nerve fibers innervating ileal smooth muscle and mucosa, and in enteroendocrine cells. Some neurons coexpressed PAR-2- and choline acetyltransferase-like immunoreactivity. These results indicate that PAR-2 is expressed on cholinergic and noncholinergic submucosal neurons in porcine ileum. PAR-2 agonists stimulate active anion secretion by a neurogenic mechanism that is modulated by prostanoids and opioids. These receptors may have a potentially important role in intestinal neuroimmunomodulation.

1 This study was funded in part by National Institutes of Health Grant DA-10200 (to D.R.B.) and NIH Grants DK-57840, DK-39957, and DK-43207, and an award from the Crohn's and Colitis Foundation of America (to N.W.B). Salary support for B.T.G. and A.K-N. was provided by Alcohol, Drug Abuse, and Mental Health Administration/National Institute on Drug Abuse Psychoneuroimmunology and Substance Abuse training Grant T32 DA07239.

0022-3565/00/2951-0410$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2000 by The American Society for Pharmacology and Experimental Therapeutics


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