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One type of SUI is due to low intraurethral pressure caused by the disabled contraction of urethral smooth muscle (USM). However, the molecular mechanisms underlying the motility of USM remain unknown. Here, we show that USM represents spontaneous tone after stretching in humans and mice. Deletion of TMEM16A in the smooth muscle of mice abolishes spontaneous urethral tone. Furthermore, Cl<jats:sub>Ca<\/jats:sub> currents and [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub> in TMEM16A<jats:sup>SMKO<\/jats:sup> mice were largely impaired. Inhibitors of ryanodine receptor (RyR), TMEM16A encoded calcium\u2010activated chloride channel (Cl<jats:sub>Ca<\/jats:sub>) and L\u2010type voltage\u2010dependent calcium channel (VDCC) fully prevented spontaneous tone accompanied by a significant decrease of intracellular calcium concentration ([Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub>). In summary, RyR\u2013Cl<jats:sub>Ca<\/jats:sub>\u2013VDCC signaling contributes to spontaneous USM tone. This finding may provide a new promising approach for women with stress SUI who reject surgery.<\/jats:p>","DOI":"10.1002\/jcp.28892","type":"journal-article","created":{"date-parts":[[2019,6,4]],"date-time":"2019-06-04T05:31:46Z","timestamp":1559626306000},"page":"23256-23267","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["The RyR\u2013Cl<sub>Ca<\/sub>\u2013VDCC axis contributes to spontaneous tone in urethral smooth muscle"],"prefix":"10.1002","volume":"234","author":[{"given":"Mei","family":"Feng","sequence":"first","affiliation":[{"name":"Central Laboratory Shandong Provincial Hospital Affiliated to Shandong University Jinan China"},{"name":"Department of Microbiology and Physiological Systems University of Massachusetts Medical School Worcester Massachusetts"},{"name":"Central Laboratory Shandong Provincial Hospital Affiliated to Shandong First Medical University Jinan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaoyang","family":"Wang","sequence":"additional","affiliation":[{"name":"Operating Room Jinan Central Hospital Affiliated to Shandong University Jinan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zheng","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Urology Shandong Provincial Hospital Affiliated to Shandong University Jinan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donghai","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Physiological Systems University of Massachusetts Medical School Worcester Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaizhi","family":"Zheng","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Physiological Systems University of Massachusetts Medical School Worcester 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