{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T09:35:33Z","timestamp":1790501733974,"version":"4.1.0"},"reference-count":59,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2017,2,14]],"date-time":"2017-02-14T00:00:00Z","timestamp":1487030400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["DK078736"],"award-info":[{"award-number":["DK078736"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000097","name":"National Center for Research Resources","doi-asserted-by":"publisher","award":["1 S10 RR16871"],"award-info":[{"award-number":["1 S10 RR16871"]}],"id":[{"id":"10.13039\/100000097","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2017,3,15]]},"abstract":"<jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>The internal anal sphincter develops tone important for maintaining high anal pressure and continence. Controversy exists regarding the mechanisms underlying tone development.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>We examined the hypothesis that tone depends upon electrical slow waves (SWs) initiated in intramuscular interstitial cells of Cajal (ICC\u2010IM) by activation of Ca<jats:sup>2+<\/jats:sup>\u2010activated Cl<jats:sup>\u2212<\/jats:sup> channels (ANO1, encoded by <jats:italic>Ano1<\/jats:italic>) and voltage\u2010dependent L\u2010type Ca<jats:sup>2+<\/jats:sup> channels (Cav<jats:sub>L<\/jats:sub>, encoded by <jats:italic>Cacna1c<\/jats:italic>).<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Measurement of membrane potential and contraction indicated that ANO1 and Cav<jats:sub>L<\/jats:sub> have a central role in SW generation, phasic contractions and tone, independent of stretch.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>ANO1 expression was examined in <jats:italic>wildtype<\/jats:italic> and <jats:italic>Ano1<jats:sup>\/+egfp<\/jats:sup><\/jats:italic> mice with immunohistochemical techniques. <jats:italic>Ano1<\/jats:italic> and <jats:italic>Cacna1c<\/jats:italic> expression levels were examined by quantitative PCR in fluorescence\u2010activated cell sorting.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>ICC\u2010IM were the predominant cell type expressing ANO1 and the most likely candidate for SW generation. SWs in ICC\u2010IM are proposed to conduct to smooth muscle where Ca<jats:sup>2+<\/jats:sup> entry via Cav<jats:sub>L<\/jats:sub> results in phasic activity that sums to produce tone.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec><jats:sec><jats:title>Abstract<\/jats:title><jats:p>The mechanism underlying tone generation in the internal anal sphincter (IAS) is controversial. We examined the hypothesis that tone depends upon generation of electrical slow waves (SWs) initiated in intramuscular interstitial cells of Cajal (ICC\u2010IM) by activation of Ca<jats:sup>2+<\/jats:sup>\u2010activated Cl<jats:sup>\u2212<\/jats:sup> channels (encoded by <jats:italic>Ano1<\/jats:italic>) and voltage\u2010dependent L\u2010type Ca<jats:sup>2+<\/jats:sup> channels (encoded by <jats:italic>Cacna1c<\/jats:italic>). Phasic contractions and tone in the IAS were nearly abolished by ANO1 and Cav<jats:sub>L<\/jats:sub> antagonists. ANO1 antagonists also abolished SWs as well as transient depolarizations that persisted after addition of Cav<jats:sub>L<\/jats:sub> antagonists. Tone development in the IAS did not require stretch of muscles, and the sensitivity of contraction to ANO1 antagonists was the same in stretched <jats:italic>versus<\/jats:italic> un\u2010stretched muscles. ANO1 expression was examined in <jats:italic>wildtype<\/jats:italic> and <jats:italic>Ano1<jats:sup>\/+egfp<\/jats:sup><\/jats:italic> mice with immunohistochemical techniques. Dual labelling revealed that ANO1 expression could be resolved in ICC but not smooth muscle cells (SMCs) in the IAS and rectum. <jats:italic>Ano1<\/jats:italic>, <jats:italic>Cacna1c<\/jats:italic> and <jats:italic>Kit<\/jats:italic> gene expression were the same in extracts of IAS and rectum muscles. In IAS cells isolated with fluorescence\u2010activated cell sorting, <jats:italic>Ano1<\/jats:italic> expression was 26.5\u2010fold greater in ICC than in SMCs while <jats:italic>Cacna1c<\/jats:italic> expression was only 2\u2010fold greater in SMCs than in ICC. These data support a central role for ANO1 and Cav<jats:sub>L<\/jats:sub> in the generation of SWs and tone in the IAS. ICC\u2010IM are the probable cellular candidate for ANO1 currents and SW generation. We propose that ANO1 and Cav<jats:sub>L<\/jats:sub> collaborate to generate SWs in ICC\u2010IM followed by conduction to adjacent SMCs where phasic calcium entry through Cav<jats:sub>L<\/jats:sub> sums to produce tone.<\/jats:p><\/jats:sec>","DOI":"10.1113\/jp273618","type":"journal-article","created":{"date-parts":[[2017,1,5]],"date-time":"2017-01-05T01:52:54Z","timestamp":1483581174000},"page":"2021-2041","source":"Crossref","is-referenced-by-count":60,"title":["ANO1 in intramuscular interstitial cells of Cajal plays a key role in the generation of slow waves and tone in the internal anal sphincter"],"prefix":"10.1113","volume":"595","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2871-3825","authenticated-orcid":false,"given":"C. A.","family":"Cobine","sequence":"first","affiliation":[{"name":"Department of Physiology and Cell Biology, University of Nevada Reno School of Medicine  Reno NV 89557 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E. 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