Anoctamin 1/TMEM16A controls intestinal Cl− secretion induced by carbachol and cholera toxin

• Published in: Experimental & molecular medicine Vol. 51; no. 8; pp. 1 - 14
• Main Authors: Lee, Byeongjun, Hong, Gyu-Sang, Lee, Sung Hoon, Kim, Hyungsup, Kim, Ajung, Hwang, Eun Mi, Kim, Jiyoon, Lee, Min Goo, Yang, Jin-Young, Kweon, Mi-Na, Tse, Chung-Ming, Mark, Donowitz, Oh, Uhtaek
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 05.08.2019; Springer Nature B.V; Nature Publishing Group; 생화학분자생물학회
• Subjects: 13/1; 13/95; 42/41; 631/443; 64/60; 692/420; 9/74; Animals; Anoctamin-1 - genetics; Anoctamin-1 - physiology; Biomedical and Life Sciences; Biomedicine; Calcium - metabolism; Calcium channels; Calcium chloride; Carbachol; Carbachol - pharmacology; Chloride channels (calcium-gated); Chloride Channels - genetics; Chloride Channels - physiology; Chlorides - metabolism; Cholera; Cholera toxin; Cholera Toxin - pharmacology; Colitis; Colitis - chemically induced; Colitis - genetics; Colitis - metabolism; Colitis - pathology; Colon; Colorectal carcinoma; Cyclic AMP; Dextran; Epithelium; Female; Inflammatory bowel disease; Intestinal Mucosa - drug effects; Intestinal Mucosa - metabolism; Intestine; Intestines - drug effects; Male; Medical Biochemistry; Mice; Mice, Knockout; Molecular Medicine; Secretion; Secretory Pathway - drug effects; Secretory Pathway - genetics; Sodium; Sodium sulfate; Stem Cells; Up-Regulation - drug effects; 생화학
• ISSN: 1226-3613; 2092-6413
• DOI: 10.1038/s12276-019-0287-2

Calcium-activated chloride channels (CaCCs) mediate numerous physiological functions and are best known for the transport of electrolytes and water in epithelia. In the intestine, CaCC currents are considered necessary for the secretion of fluid to protect the intestinal epithelium. Although genetic ablation of ANO1/TMEM16A, a gene encoding a CaCC, reduces the carbachol-induced secretion of intestinal fluid, its mechanism of action is still unknown. Here, we confirm that ANO1 is essential for the secretion of intestinal fluid. Carbachol-induced transepithelial currents were reduced in the proximal colon of Ano1- deficient mice. Surprisingly, cholera toxin-induced and cAMP-induced fluid secretion, believed to be mediated by CFTR, were also significantly reduced in the intestine of Ano1 -deficient mice. ANO1 is largely expressed in the apical membranes of intestines, as predicted for CaCCs. The Ano1 -deficient colons became edematous under basal conditions and had a greater susceptibility to dextran sodium sulfate-induced colitis. However, Ano1 depletion failed to affect tumor development in a model of colorectal cancer. We thus conclude that ANO1 is necessary for cAMP- and carbachol-induced Cl − secretion in the intestine, which is essential for the protection of the intestinal epithelium from colitis. Colitis: Intestinal membrane protein implicated in defective fluid secretion An ion channel, a membrane protein allowing ion transport, that controls the flow of chloride is needed for proper secretion of protective fluids in the intestine. Uhtaek Oh from the Korea Institute of Science & Technology in Seoul, South Korea, and colleagues showed that cells lining the intestinal surface express a calcium-activated chloride channel called anoctamin-1 (ANO1) that regulates fluid secretion in the gut. Compared to control animals, ANO1-deficient mice released less fluid into their intestines following exposure to a diarrhea-inducing toxin or to a chloride transport–stimulating signaling molecule. This fluid secretion was previously thought to be mediated via a different ion channel. The ANO1-deficient mice accumulated fluid within colonic tissues, which increased their susceptibility to colitis. The findings point to ANO1 activation as a potential therapeutic strategy for treating colitis.