{"title":"Protective role of M<sub>3</sub> muscarinic acetylcholine receptor in indomethacin-induced small intestinal injury.","authors":"Yoko Igarashi-Hisayoshi, Eikichi Ihara, Xiaopeng Bai, Yoshimasa Tanaka, Haruei Ogino, Takatoshi Chinen, Yasushi Taguchi, Yoshihiro Ogawa","doi":"10.1007/s00109-024-02474-0","DOIUrl":null,"url":null,"abstract":"<p><p>EP<sub>4</sub> prostanoid receptor (EP<sub>4</sub>R) contributes to the intestinal epithelial Cl<sup>-</sup> secretion, and inhibition of prostaglandin E (PGE) production by non-steroidal anti-inflammatory drugs (NSAIDs) plays a central role in NSAID-induced enteropathy. Although M<sub>3</sub> muscarinic acetylcholine receptor (M<sub>3</sub>R) also contributes to the intestinal epithelial Cl<sup>-</sup> secretion, it remains unclear whether M<sub>3</sub>R is involved in NSAID-induced enteropathy due to a lack of selective agents. The present study explored how M<sub>3</sub>R is involved in the regulation of the intestinal epithelial Cl<sup>-</sup> secretion and its pathophysiological role in NSAID-induced enteropathy. Using the novel highly-selective M<sub>3</sub> positive allosteric modulator PAM-369 that we recently developed, we evaluated the role of M<sub>3</sub>R in the intestinal epithelial secretion ex vivo by measuring the short circuit current (Isc) of intestinal epithelium with a Ussing chamber system and examined whether or not M<sub>3</sub>R protects against small intestinal injury in indomethacin-treated mice. Both the PGE<sub>1</sub> derivative misoprostol and carbachol similarly increased the Isc in a concentration-dependent manner. The Isc increases were abolished either by receptor antagonists (an EP<sub>4</sub>R antagonist and a M<sub>3</sub>R antagonist, respectively) or by removal of extracellular Cl<sup>-</sup>. PAM-369 enhanced the carbachol-induced Isc by potentiating M<sub>3</sub>R, which could contribute to enhanced intestinal epithelial secretion. Treatment with PAM-369 ameliorated small intestinal injury in indomethacin-treated mice. Importantly, the M<sub>3</sub>R expression was significantly up-regulated, and PAM-369 potentiation of M<sub>3</sub>R was augmented in indomethacin-treated mice compared to untreated mice. These findings show that M<sub>3</sub>R plays a role in maintaining the intestinal epithelial secretion, which could contribute to protection against indomethacin-induced small intestinal injury. M<sub>3</sub>R is a promising target for treating or preventing NSAID-induced enteropathy. KEY MESSAGES: PAM-369, the M<sub>3</sub> positive allosteric modulator, was used to potentiate M<sub>3</sub>R. PAM-369 enhanced carbachol-induced Isc in mouse ileum. PAM-369 ameliorated small intestinal injury in indomethacin-treated mice. M<sub>3</sub>R is a promising target for treating or preventing NSAID-induced enteropathy.</p>","PeriodicalId":50127,"journal":{"name":"Journal of Molecular Medicine-Jmm","volume":null,"pages":null},"PeriodicalIF":4.8000,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Molecular Medicine-Jmm","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s00109-024-02474-0","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/8/22 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"GENETICS & HEREDITY","Score":null,"Total":0}
引用次数: 0
Abstract
EP4 prostanoid receptor (EP4R) contributes to the intestinal epithelial Cl- secretion, and inhibition of prostaglandin E (PGE) production by non-steroidal anti-inflammatory drugs (NSAIDs) plays a central role in NSAID-induced enteropathy. Although M3 muscarinic acetylcholine receptor (M3R) also contributes to the intestinal epithelial Cl- secretion, it remains unclear whether M3R is involved in NSAID-induced enteropathy due to a lack of selective agents. The present study explored how M3R is involved in the regulation of the intestinal epithelial Cl- secretion and its pathophysiological role in NSAID-induced enteropathy. Using the novel highly-selective M3 positive allosteric modulator PAM-369 that we recently developed, we evaluated the role of M3R in the intestinal epithelial secretion ex vivo by measuring the short circuit current (Isc) of intestinal epithelium with a Ussing chamber system and examined whether or not M3R protects against small intestinal injury in indomethacin-treated mice. Both the PGE1 derivative misoprostol and carbachol similarly increased the Isc in a concentration-dependent manner. The Isc increases were abolished either by receptor antagonists (an EP4R antagonist and a M3R antagonist, respectively) or by removal of extracellular Cl-. PAM-369 enhanced the carbachol-induced Isc by potentiating M3R, which could contribute to enhanced intestinal epithelial secretion. Treatment with PAM-369 ameliorated small intestinal injury in indomethacin-treated mice. Importantly, the M3R expression was significantly up-regulated, and PAM-369 potentiation of M3R was augmented in indomethacin-treated mice compared to untreated mice. These findings show that M3R plays a role in maintaining the intestinal epithelial secretion, which could contribute to protection against indomethacin-induced small intestinal injury. M3R is a promising target for treating or preventing NSAID-induced enteropathy. KEY MESSAGES: PAM-369, the M3 positive allosteric modulator, was used to potentiate M3R. PAM-369 enhanced carbachol-induced Isc in mouse ileum. PAM-369 ameliorated small intestinal injury in indomethacin-treated mice. M3R is a promising target for treating or preventing NSAID-induced enteropathy.
期刊介绍:
The Journal of Molecular Medicine publishes original research articles and review articles that range from basic findings in mechanisms of disease pathogenesis to therapy. The focus includes all human diseases, including but not limited to:
Aging, angiogenesis, autoimmune diseases as well as other inflammatory diseases, cancer, cardiovascular diseases, development and differentiation, endocrinology, gastrointestinal diseases and hepatology, genetics and epigenetics, hematology, hypoxia research, immunology, infectious diseases, metabolic disorders, neuroscience of diseases, -omics based disease research, regenerative medicine, and stem cell research.
Studies solely based on cell lines will not be considered. Studies that are based on model organisms will be considered as long as they are directly relevant to human disease.