Irsogladine activates gap-junctional intercellular communication through M1 muscarinic acetylcholine receptor.
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.
Ueda
F
F
Discovery Research Laboratories II, Nippon Shinyaku Co. Ltd., Kyoto, Japan.
Ban
K
K
Ishima
T
T
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*
D000897:Anti-Ulcer Agents; D011976:Receptors, Muscarinic; D014227:Triazines; D008455:(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethylammonium Chloride; D007545:Isoproterenol; C041836:irsogladine