Up-regulated PAR-2-mediated salivary secretion in mice deficient in muscarinic acetylcholine receptor subtypes.
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 [Ca(2+)](i) submandibular gland (SMG) acinar cells in wild-type (WT) mice and mice lacking M(3) or both M(1) and M(3) 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. Ca(2+) imaging in WT acinar cells and beta-galactosidase staining in PAR-2KO mice, in which the beta-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 Ca(2+) response were enhanced in mice lacking M(3) or both M(1) and M(3) mAChRs, in which mAChR-stimulated secretion and Ca(2+) response in acinar cells were severely impaired. Although the mechanism underlying the enhanced PAR-2-mediated salivary secretion in M(3)-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 Ca(2+)-dependent fluid secretion, demonstrating potential usefulness of PAR-2 as a target for dry mouth treatment.
Nishiyama
Tatsuaki
T
Department of Pathology, Tsurumi University School of Dental Medicine, Tsurumi-ku, Yokohama, 230-8501, Japan.
Nakamura
Takeshi
T
Obara
Kumi
K
Inoue
Hiroko
H
Mishima
Kenji
K
Matsumoto
Nagisa
N
Matsui
Minoru
M
Manabe
Toshiya
T
Mikoshiba
Katsuhiko
K
Saito
Ichiro
I
D000818:Animals; D002118:Calcium / Q000378:metabolism; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009842:Oligopeptides / Q000494:pharmacology; D010862:Pilocarpine / Q000494:pharmacology; D044464:Receptor, PAR-2 / Q000032:analysis / Q000187:drug effects / Q000502:physiology*; D011976:Receptors, Muscarinic / Q000145:classification / Q000502:physiology*; D012463:Saliva / Q000378:metabolism*; D013363:Submandibular Gland / Q000378:metabolism
D009842:Oligopeptides; D044464:Receptor, PAR-2; D011976:Receptors, Muscarinic; C099570:seryl-leucyl-isoleucyl-glycyl-arginyl-leucine; D010862:Pilocarpine; D007545:Isoproterenol; D002118:Calcium