RT Journal Article SR Electronic T1 Protease-Activated Receptor-2 Peptides Activate Neurokinin-1 Receptors in the Mouse Isolated Trachea JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 598 OP 605 DO 10.1124/jpet.105.097121 VO 317 IS 2 A1 Hugh T. Abey A1 David P. Fairlie A1 James D. Moffatt A1 Rowan W. Balzary A1 Thomas M. Cocks YR 2006 UL http://jpet.aspetjournals.org/content/317/2/598.abstract AB Protective roles for protease-activated receptor-2 (PAR2) in the airways including activation of epithelial chloride (Cl–) secretion are based on the use of presumably PAR2-selective peptide agonists. To determine whether PAR2 peptide-activated Cl– secretion from mouse tracheal epithelium is dependent on PAR2, changes in ion conductance across the epithelium [short-circuit current (ISC)] to PAR2 peptides were measured in Ussing chambers under voltage clamp. In addition, epithelium- and endothelium-dependent relaxations to these peptides were measured in two established PAR2 bioassays, isolated ring segments of mouse trachea and rat thoracic aorta, respectively. Apical application of the PAR2 peptide SLIGRL caused increases in ISC, which were inhibited by three structurally different neurokinin receptor-1 (NK1R) antagonists and inhibitors of Cl– channels but not by capsaicin, the calcitonin gene-related peptide (CGRP) receptor antagonist CGRP8–37, or the nonselective cyclooxygenase inhibitor indomethacin. Only high concentrations of trypsin caused an increase in ISC but did not affect the responses to SLIGRL. Relaxations to SLIGRL in the trachea and aorta were unaffected by the NK1R antagonist nolpitantium (SR 140333) but were abolished by trypsin desensitization. The rank order of potency for a range of peptides in the trachea ISC assay was 2-furoyl-LIGRL > SLCGRL > SLIGRL = SLIGRT > LSIGRL compared with 2-furoyl-LIGRL > SLIGRL > SLIGRT > SLCGRL (LSIGRL inactive) in the aorta relaxation assay. In the mouse trachea, PAR2 peptides activate both epithelial NK1R coupled to Cl– secretion and PAR2 coupled to prostaglandin E2-mediated smooth muscle relaxation. Such a potential lack of specificity of these commonly used peptides needs to be considered when roles for PAR2 in airway function in health and disease are determined. The American Society for Pharmacology and Experimental Therapeutics