TY - JOUR T1 - Up-Regulated PAR-2-Mediated Salivary Secretion in Mice Deficient in Muscarinic Acetylcholine Receptor Subtypes JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 516 LP - 524 DO - 10.1124/jpet.106.113092 VL - 320 IS - 2 AU - Tatsuaki Nishiyama AU - Takeshi Nakamura AU - Kumi Obara AU - Hiroko Inoue AU - Kenji Mishima AU - Nagisa Matsumoto AU - Minoru Matsui AU - Toshiya Manabe AU - Katsuhiko Mikoshiba AU - Ichiro Saito Y1 - 2007/02/01 UR - http://jpet.aspetjournals.org/content/320/2/516.abstract N2 - Protease-activated receptor-2 (PAR-2) is expressed in the salivary glands and is expected to be a new target for the treatment of exocrine dysfunctions, such as dry mouth; however, the salivary secretory mechanism mediated by PAR-2 remains to be elucidated. Therefore, mechanism of the PAR-2-mediated salivary secretion was investigated in this study. We found that a PAR-2 agonist peptide, SLIGRL-OH, induced salivary flow in vivo and dose-dependent increase in [Ca2+]i submandibular gland (SMG) acinar cells in wild-type (WT) mice and mice lacking M3 or both M1 and M3 muscarinic acetylcholine receptors (mAChRs), whereas secretions in PAR-2 knockout (PAR-2KO) mice were completely abolished. The saliva composition secreted by SLIGRL-OH was similar to that secreted by mAChR stimulation. Ca2+ imaging in WT acinar cells and β-galactosidase staining in PAR-2KO mice, in which the β-galactosidase gene (LacZ) was incorporated into the disrupted gene, revealed a nonubiquitous, sporadic distribution of PAR-2 in the SMG. Furthermore, compared with the secretion in WT mice, PAR-2-mediated salivary secretion and Ca2+ response were enhanced in mice lacking M3 or both M1 and M3 mAChRs, in which mAChR-stimulated secretion and Ca2+ response in acinar cells were severely impaired. Although the mechanism underlying the enhanced PAR-2-mediated salivary secretion in M3-deficient mice is not clear, the result suggests the presence of some compensatory mechanism involving PAR-2 in the salivary glands deficient in cholinergic activation. These results indicate that PAR-2 present in the salivary glands mediates Ca2+-dependent fluid secretion, demonstrating potential usefulness of PAR-2 as a target for dry mouth treatment. The American Society for Pharmacology and Experimental Therapeutics ER -