QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.106.113092v1 320/2/516    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Nishiyama, T. Articles by Saito, I. Search for Related Content PubMed PubMed Citation Articles by Nishiyama, T. Articles by Saito, I.

CELLULAR AND MOLECULAR

Up-Regulated PAR-2-Mediated Salivary Secretion in Mice Deficient in Muscarinic Acetylcholine Receptor Subtypes

Department of Pathology, Tsurumi University School of Dental Medicine, Yokohama, Japan (T.Ni., K.O., H.I., K.Mis., I.S.); Sjogren's Syndrome Project, Shinanomachi Research Park, Keio University, Tokyo, Japan (T.Ni., I.S.); Calcium Oscillation Project, International Cooperative Research Project, Japan Science and Technology Agency, Minato-ku, Tokyo, Japan (T.Na., K.Mik.); and Divisions of Molecular Neurobiology (N.M., K.Mik.) and Neuronal Network (M.M., T.M.,), Department of Basic Medical Sciences, Institute of Medical Science, University of Tokyo, Tokyo, Japan

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 -galactosidase staining in PAR-2KO mice, in which the -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.

Address correspondence to: Dr. Ichiro Saito, Department of Pathology, Tsurumi University School of Dental Medicine, 2-1-3 Tsurumi, Tsurumi-ku, Yokohama, 230-8501, Japan. E-mail: saito-i{at}tsurumi-u.ac.jp