title: Irsogladine activates gap-junctional intercellular communication through M1 muscarinic acetylcholine receptor.
abstract: Irsogladine, an agent that protects gastric mucosa against various ulcerogenic stimuli through increasing cyclic AMP in surface mucous cells, has been reported to dose-dependently (10(-7) to 10(-5) M) facilitate gap-junctional intercellular communication (GJIC) in gastric epithelial cells. The beta adrenergic agonist, isoproterenol, stimulates GJIC in resting cells and inhibits GJIC in cells activated by 3-isobutyl-1-methylxanthine. In this study, we investigated whether irsogladine acts on GJIC in a manner similar to that shown by isoproterenol. Irsogladine, which bound to M1 muscarinic acetylcholine receptors (mAChR), did not inhibit, but failed to further facilitate the 3-isobutyl-1-methylxanthine-enhanced GJIC, measured by Lucifer yellow transfer. The enhancement of GJIC by irsogladine was inhibited by the M1 mAChR antagonist, pirenzepine. A selective M1 mAChR agonist, McN-A-343, enhanced GJIC. Isoproterenol (10(-8) to 10(-6) M), which alone did not affect GJIC, inhibited the GJIC enhanced by 10(-5) M irsogladine. Conversely, 10(-10) to 10(-6) M irsogladine, which alone did not affect GJIC, inhibited the GJIC enhanced by 10(-5) M isoproterenol. McN-A-343 also converted the action of 10(-5) M isoproterenol from facilitation to inhibition of GJIC. These results indicate that GJIC is heterologously down-regulated by cross-talk between M1 mAChR and beta adrenergic receptors. In addition, the effects of irsogladine and isoproterenol at low concentrations suggest the involvement of another mechanism for down-regulating GJIC.
authors.affiliation: Discovery Research Laboratories II, Nippon Shinyaku Co. Ltd., Kyoto, Japan.
authors.forename: F
authors.initials: F
authors.lastname: Ueda
authors.forename: K
authors.initials: K
authors.lastname: Ban
authors.forename: T
authors.initials: T
authors.lastname: Ishima
mesh_terms: D008455:(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethylammonium Chloride / Q000494:pharmacology; D000818:Animals; D000897:Anti-Ulcer Agents / Q000494:pharmacology*; D002450:Cell Communication / Q000187:drug effects*; D017629:Gap Junctions / Q000187:drug effects*; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D011976:Receptors, Muscarinic / Q000187:drug effects*; D014227:Triazines / Q000494:pharmacology*
chemical_list: D000897:Anti-Ulcer Agents; D011976:Receptors, Muscarinic; D014227:Triazines; D008455:(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethylammonium Chloride; D007545:Isoproterenol; C041836:irsogladine