Abstract
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.
Footnotes
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The Sjogren's Syndrome Project of Keio University was supported by Kowa Co., Ltd. This study was funded by Pharmacia; Detrol LA Research Grant Program was supported by Pfizer; The Industrial Technology Research Grant Program 02A09001a was supported by The New Energy and Industrial Technology Development Organization of Japan, and Grant-in-aid for Scientific Research on Priority Areas 16067101 was supported by The Ministry of Education, Culture, Sports, Science and Technology.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.106.113092.
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ABBREVIATIONS: PAR-2, protease-activated receptor-2; SMG, submandibular gland; WT, wild type; mAChRs, muscarinic acetylcholine receptors; PAR-2KO, PAR-2 knockout; KO, knockout; SS, Sjogren's syndrome; TG, transgenic mice; HE, hematoxylin and eosin; BSS, balanced salt solution; BSA, bovine serum albumin; CCh, carbachol.
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↵1 Deceased in July 23, 2006.
- Received September 1, 2006.
- Accepted October 30, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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