TY - JOUR T1 - Proteinase-Activated Receptor-2-Mediated Relaxation in Mouse Tracheal and Bronchial Smooth Muscle: Signal Transduction Mechanisms and Distinct Agonist Sensitivity JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 402 LP - 410 DO - 10.1124/jpet.104.068387 VL - 311 IS - 1 AU - Atsufumi Kawabata AU - Satoko Kubo AU - Tsuyoshi Ishiki AU - Naoyuki Kawao AU - Fumiko Sekiguchi AU - Ryotaro Kuroda AU - Morley D. Hollenberg AU - Toru Kanke AU - Naohiro Saito Y1 - 2004/10/01 UR - http://jpet.aspetjournals.org/content/311/1/402.abstract N2 - We characterized the tracheal and bronchial relaxation caused by proteinase-activated receptor-2 (PAR-2) activation in ddY mice and/or in wild-type and PAR-2-knockout mice of C57BL/6 background. Ser-Leu-Ile-Gly-Arg-Leu-amide (SLIGRL-NH2) and Thr-Phe-Leu-Leu-Arg-amide, PAR-2- and PAR-1-activating peptides, respectively, caused relaxation in the isolated ddY mouse trachea and main bronchus. The relaxation was abolished by specific inhibitors of cyclooxygenase (COX)-1, COX-2, mitogen-activated protein kinase kinase (MEK), and p38 MAP kinase. The MEK and p38 MAP kinase inhibitors did not affect prostaglandin E2-induced relaxation. Inhibitors of cytosolic Ca2+-dependent phospholipase A2 (PLA), Ca2+-independent PLA2, diacylglycerol lipase, tyrosine kinase, and protein kinase C exhibited no or only minor inhibitory effects on the PAR-mediated relaxation. Trypsin, a PAR-2 activator, and 2-furoyl-Leu-Ile-Gly-Arg-Leu-amide, a potent PAR-2-activating peptide, in addition to SLIGRL-NH2, caused airway relaxation in wild-type C57BL/6 mice, as in ddY mice. In PAR-2-knockout mice, the peptide effects were absent and the potency of trypsin decreased. Desensitization of PAR-2 and/or PAR-1greatly suppressed the relaxant effect of trypsin. The bronchial and tracheal tissues displayed distinct sensitivities toward trypsin and the PAR-2-activating peptides. Our data indicate an involvement of both COX-1 and COX-2, and the MEK-extracellular signal-regulated kinase and p38 MAP kinase signaling pathways in the PAR-2- and PAR-1-triggered relaxation of mouse airway tissue, and substantiate a role for PAR-2 in regulating both the trachea and bronchial responsiveness in the mouse lung. The American Society for Pharmacology and Experimental Therapeutics ER -