{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T02:50:57Z","timestamp":1777517457425,"version":"3.51.4"},"reference-count":57,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2016,4,22]],"date-time":"2016-04-22T00:00:00Z","timestamp":1461283200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2016,4,22]],"date-time":"2016-04-22T00:00:00Z","timestamp":1461283200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Commun"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Smooth muscle sphincters exhibit basal tone and control passage of contents through organs such as the gastrointestinal tract; loss of this tone leads to disorders such as faecal incontinence. However, the molecular mechanisms underlying this tone remain unknown. Here, we show that deletion of myosin light-chain kinases (MLCK) in the smooth muscle cells from internal anal sphincter (IAS-SMCs) abolishes basal tone, impairing defecation. Pharmacological regulation of ryanodine receptors (RyRs), L-type voltage-dependent Ca<jats:sup>2+<\/jats:sup>channels (VDCCs) or TMEM16A Ca<jats:sup>2+<\/jats:sup>-activated Cl<jats:sup>\u2212<\/jats:sup>channels significantly changes global cytosolic Ca<jats:sup>2+<\/jats:sup>concentration ([Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub>) and the tone. TMEM16A deletion in IAS-SMCs abolishes the effects of modulators for TMEM16A or VDCCs on a RyR-mediated rise in global [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub>and impairs the tone and defecation. Hence, MLCK activation in IAS-SMCs caused by a global rise in [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub>via a RyR-TMEM16A-VDCC signalling module sets the basal tone. Targeting this module may lead to new treatments for diseases like faecal incontinence.<\/jats:p>","DOI":"10.1038\/ncomms11358","type":"journal-article","created":{"date-parts":[[2016,4,22]],"date-time":"2016-04-22T10:35:54Z","timestamp":1461321354000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["The molecular basis of the genesis of basal tone in internal anal sphincter"],"prefix":"10.1038","volume":"7","author":[{"given":"Cheng-Hai","family":"Zhang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pei","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dong-Hai","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cai-Ping","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wei","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xin","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chen","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wei-Qi","family":"He","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yan-Ning","family":"Qiao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tao","family":"Tao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jie","family":"Sun","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ya-Jing","family":"Peng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ping","family":"Lu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kaizhi","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Siobhan M.","family":"Craige","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lawrence M.","family":"Lifshitz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John F.","family":"Keaney Jr","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kevin E.","family":"Fogarty","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ronghua","family":"ZhuGe","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Min-Sheng","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2016,4,22]]},"reference":[{"key":"BFncomms11358_CR1","unstructured":"Vander, A., Sherman, J. & Luciano, D. Human Physiology: The Mechanisms of Body Function 6th edn, International Edition McGraw-Hill international editions (1994) ."},{"key":"BFncomms11358_CR2","doi-asserted-by":"publisher","first-page":"50","DOI":"10.1111\/j.1365-2982.2005.00659.x","volume":"17","author":"S Rattan","year":"2005","unstructured":"Rattan, S. The internal anal sphincter: regulation of smooth muscle tone and relaxation. Neurogastroenterol. Motil. 17, 50\u201359 (2005) .","journal-title":"Neurogastroenterol. Motil."},{"key":"BFncomms11358_CR3","doi-asserted-by":"publisher","first-page":"345","DOI":"10.1146\/annurev.physiol.68.040504.094707","volume":"68","author":"KS Murthy","year":"2006","unstructured":"Murthy, K. S. Signaling for contraction and relaxation in smooth muscle of the gut. Annu. Rev. Physiol. 68, 345\u2013374 (2006) .","journal-title":"Annu. Rev. Physiol."},{"key":"BFncomms11358_CR4","doi-asserted-by":"publisher","first-page":"1325","DOI":"10.1152\/physrev.00023.2003","volume":"83","author":"AP Somlyo","year":"2003","unstructured":"Somlyo, A. P. & Somlyo, A. V. Ca2+ sensitivity of smooth muscle and nonmuscle myosin II: modulated by G proteins, kinases, and myosin phosphatase. Physiol. Rev. 83, 1325\u20131358 (2003) .","journal-title":"Physiol. Rev."},{"key":"BFncomms11358_CR5","doi-asserted-by":"publisher","first-page":"G664","DOI":"10.1152\/ajpgi.00430.2011","volume":"302","author":"S Rattan","year":"2012","unstructured":"Rattan, S. & Singh, J. RhoA\/ROCK pathway is the major molecular determinant of basal tone in intact human internal anal sphincter. Am. J. Physiol. Gastrointest. Liver Physiol. 302, G664\u2013G675 (2012) .","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"BFncomms11358_CR6","doi-asserted-by":"publisher","first-page":"G1747","DOI":"10.1152\/ajpgi.00438.2006","volume":"292","author":"CA Patel","year":"2007","unstructured":"Patel, C. A. & Rattan, S. Cellular regulation of basal tone in internal anal sphincter smooth muscle by RhoA\/ROCK. Am. J. Physiol. Gastrointest. Liver Physiol. 292, G1747\u2013G1756 (2007) .","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"BFncomms11358_CR7","doi-asserted-by":"publisher","first-page":"G830","DOI":"10.1152\/ajpgi.00130.2006","volume":"291","author":"CA Patel","year":"2006","unstructured":"Patel, C. A. & Rattan, S. Spontaneously tonic smooth muscle has characteristically higher levels of RhoA\/ROK compared with the phasic smooth muscle. Am. J. Physiol. Gastrointest. Liver Physiol. 291, G830\u2013G837 (2006) .","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"BFncomms11358_CR8","doi-asserted-by":"publisher","first-page":"G1041","DOI":"10.1152\/ajpgi.00356.2007","volume":"294","author":"B Mcdonnell","year":"2008","unstructured":"Mcdonnell, B., Hamilton, R., Fong, M., Ward, S. M. & Keef, K. D. Functional evidence for purinergic inhibitory neuromuscular transmission in the mouse internal anal sphincter. Am. J. Physiol. Gastrointest. Liver Physiol. 294, G1041\u2013G1051 (2008) .","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"BFncomms11358_CR9","doi-asserted-by":"publisher","first-page":"1575","DOI":"10.1016\/S0016-5085(97)70039-8","volume":"112","author":"S Chakder","year":"1997","unstructured":"Chakder, S., Mchugh, K. M. & Rattan, S. Inhibitory neurotransmission in lethal spotted mutant mice: a model for Hirschsprung's disease. Gastroenterology 112, 1575\u20131585 (1997) .","journal-title":"Gastroenterology"},{"key":"BFncomms11358_CR10","doi-asserted-by":"publisher","first-page":"3813","DOI":"10.1113\/jphysiol.2014.272542","volume":"592","author":"KA Hall","year":"2014","unstructured":"Hall, K. A., Ward, S. M., Cobine, C. A. & Keef, K. D. Spatial organization and coordination of slow waves in the mouse anorectum. J. Physiol. 592, 3813\u20133829 (2014) .","journal-title":"J. Physiol."},{"key":"BFncomms11358_CR11","doi-asserted-by":"publisher","first-page":"G643","DOI":"10.1152\/ajpgi.00260.2009","volume":"298","author":"CA Cobine","year":"2010","unstructured":"Cobine, C. A. et al. Interstitial cells of Cajal in the cynomolgus monkey rectoanal region and their relationship to sympathetic and nitrergic nerves. Am. J. Physiol. Gastrointest. Liver Physiol. 298, G643\u2013G656 (2010) .","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"BFncomms11358_CR12","doi-asserted-by":"publisher","first-page":"1456","DOI":"10.1053\/j.gastro.2013.02.045","volume":"144","author":"WQ He","year":"2013","unstructured":"He, W. Q. et al. Altered contractile phenotypes of intestinal smooth muscle in mice deficient in myosin phosphatase target subunit 1. Gastroenterology 144, 1456\u20131465 (2013) .","journal-title":"Gastroenterology"},{"key":"BFncomms11358_CR13","doi-asserted-by":"publisher","first-page":"610","DOI":"10.1053\/j.gastro.2008.05.032","volume":"135","author":"WQ He","year":"2008","unstructured":"He, W. Q. et al. Myosin light chain kinase is central to smooth muscle contraction and required for gastrointestinal motility in mice. Gastroenterology 135, 610\u2013620 (2008) .","journal-title":"Gastroenterology"},{"key":"BFncomms11358_CR14","first-page":"17","volume":"285","author":"WC Zhang","year":"2010","unstructured":"Zhang, W. C. et al. Myosin light chain kinase is necessary for tonic airway smooth muscle contraction. J. Biol. Chem. 285, 17\u201319 (2010) .","journal-title":"J. Biol. Chem."},{"key":"BFncomms11358_CR15","first-page":"A824","volume":"114","author":"S Rao","year":"1998","unstructured":"Rao, S., Kempf, J. & Stessman, M. Anal seepage: sphincter dysfunction or incomplete evaluation? Gastroenterology 114, A824 (1998) .","journal-title":"Gastroenterology"},{"key":"BFncomms11358_CR16","doi-asserted-by":"publisher","first-page":"S14","DOI":"10.1053\/j.gastro.2003.10.013","volume":"126","author":"SS Rao","year":"2004","unstructured":"Rao, S. S. Pathophysiology of adult fecal incontinence. Gastroenterology 126, S14\u2013S22 (2004) .","journal-title":"Gastroenterology"},{"key":"BFncomms11358_CR17","doi-asserted-by":"publisher","first-page":"937","DOI":"10.1111\/j.1365-2982.2007.00982.x","volume":"19","author":"CA Cobine","year":"2007","unstructured":"Cobine, C. A., Fong, M., Hamilton, R. & Keef, K. D. Species dependent differences in the actions of sympathetic nerves and noradrenaline in the internal anal sphincter. Neurogastroenterol. Motil. 19, 937\u2013945 (2007) .","journal-title":"Neurogastroenterol. Motil."},{"key":"BFncomms11358_CR18","first-page":"734","volume":"40","author":"W Zheng","year":"1991","unstructured":"Zheng, W., Rampe, D. & Triggle, D. J. Pharmacological, radioligand binding, and electrophysiological characteristics of FPL 64176, a novel nondihydropyridine Ca2+ channel activator, in cardiac and vascular preparations. Mol. Pharmacol. 40, 734\u2013741 (1991) .","journal-title":"Mol. Pharmacol."},{"key":"BFncomms11358_CR19","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1529\/biophysj.104.051714","volume":"88","author":"SI McDonough","year":"2005","unstructured":"McDonough, S. I., Mori, Y. & Bean, B. P. FPL 64176 modification of CaV1.2L-type calcium channels: dissociation of effects on ionic current and gating current. Biophys. J. 88, 211\u2013223 (2005) .","journal-title":"Biophys. J."},{"key":"BFncomms11358_CR20","doi-asserted-by":"publisher","first-page":"2203","DOI":"10.1074\/jbc.M109.067546","volume":"285","author":"R Zhuge","year":"2010","unstructured":"Zhuge, R., Bao, R., Fogarty, K. E. & Lifshitz, L. M. Ca2+ sparks act as potent regulators of excitation-contraction coupling in airway smooth muscle. J. Biol. Chem. 285, 2203\u20132210 (2010) .","journal-title":"J. Biol. Chem."},{"key":"BFncomms11358_CR21","doi-asserted-by":"publisher","first-page":"861","DOI":"10.1007\/s00424-013-1357-2","volume":"466","author":"S Bulley","year":"2013","unstructured":"Bulley, S. & Jaggar, J. H. Cl\u2212 channels in smooth muscle cells. Pflug. Arch. 466, 861\u2013872 (2013) .","journal-title":"Pflug. Arch."},{"key":"BFncomms11358_CR22","doi-asserted-by":"publisher","first-page":"G115","DOI":"10.1152\/ajpgi.1992.263.1.G115","volume":"263","author":"JK Saha","year":"1992","unstructured":"Saha, J. K., Sengupta, J. N. & Goyal, R. K. Role of chloride ions in lower esophageal sphincter tone and relaxation. Am. J. Physiol. Gastrointest. Liver Physiol. 263, G115\u2013G126 (1992) .","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"BFncomms11358_CR23","doi-asserted-by":"publisher","first-page":"2365","DOI":"10.1074\/jbc.M110.175109","volume":"286","author":"W Namkung","year":"2011","unstructured":"Namkung, W., Phuan, P. W. & Verkman, A. S. TMEM16A inhibitors reveal TMEM16A as a minor component of calcium-activated chloride channel conductance in airway and intestinal epithelial cells. J. Biol. Chem. 286, 2365\u20132374 (2011) .","journal-title":"J. Biol. Chem."},{"key":"BFncomms11358_CR24","doi-asserted-by":"crossref","first-page":"720","DOI":"10.1016\/S0026-895X(25)10907-3","volume":"37","author":"MM White","year":"1990","unstructured":"White, M. M. & Aylwin, M. Niflumic and flufenamic acids are potent reversible blockers of Ca2+-activated Cl- channels in Xenopus oocytes. Mol. Pharmacol. 37, 720\u2013724 (1990) .","journal-title":"Mol. Pharmacol."},{"key":"BFncomms11358_CR25","doi-asserted-by":"publisher","first-page":"4048","DOI":"10.1096\/fj.11-191627","volume":"25","author":"W Namkung","year":"2011","unstructured":"Namkung, W., Yao, Z., Finkbeiner, W. E. & Verkman, A. S. Small-molecule activators of TMEM16A, a calcium-activated chloride channel, stimulate epithelial chloride secretion and intestinal contraction. FASEB J. 25, 4048\u20134062 (2011) .","journal-title":"FASEB J."},{"key":"BFncomms11358_CR26","doi-asserted-by":"publisher","first-page":"633","DOI":"10.1126\/science.270.5236.633","volume":"270","author":"MT Nelson","year":"1995","unstructured":"Nelson, M. T. et al. Relaxation of arterial smooth muscle by calcium sparks. Science 270, 633\u2013637 (1995) .","journal-title":"Science"},{"key":"BFncomms11358_CR27","doi-asserted-by":"publisher","first-page":"C1577","DOI":"10.1152\/ajpcell.00153.2004","volume":"287","author":"R Zhuge","year":"2004","unstructured":"Zhuge, R. et al. Ca2+ spark sites in smooth muscle cells are numerous and differ in number of ryanodine receptors, large-conductance K+ channels, and coupling ratio between them. Am. J. Physiol. Cell Physiol. 287, C1577\u2013C1588 (2004) .","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"BFncomms11358_CR28","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1085\/jgp.113.2.215","volume":"113","author":"R Zhuge","year":"1999","unstructured":"Zhuge, R. et al. The influence of sarcoplasmic reticulum Ca2+ concentration on Ca2+ sparks and spontaneous transient outward currents in single smooth muscle cells. J. Gen. Physiol. 113, 215\u2013228 (1999) .","journal-title":"J. Gen. Physiol."},{"key":"BFncomms11358_CR29","doi-asserted-by":"publisher","first-page":"711","DOI":"10.1111\/j.1469-7793.1998.711ba.x","volume":"513","author":"R Zhuge","year":"1998","unstructured":"Zhuge, R., Sims, S. M., Tuft, R. A., Fogarty, K. E. & Walsh, J. V. Jr Ca2+ sparks activate K+ and Cl- channels, resulting in spontaneous transient currents in guinea-pig tracheal myocytes. J. Physiol. 513, 711\u2013718 (1998) .","journal-title":"J. Physiol."},{"key":"BFncomms11358_CR30","doi-asserted-by":"publisher","first-page":"21413","DOI":"10.1073\/pnas.0911935106","volume":"106","author":"F Huang","year":"2009","unstructured":"Huang, F. et al. Studies on expression and function of the TMEM16A calcium-activated chloride channel. Proc. Natl Acad. Sci. USA 106, 21413\u201321418 (2009) .","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"BFncomms11358_CR31","doi-asserted-by":"publisher","first-page":"1210","DOI":"10.1038\/nature07313","volume":"455","author":"YD Yang","year":"2008","unstructured":"Yang, Y. D. et al. TMEM16A confers receptor-activated calcium-dependent chloride conductance. Nature 455, 1210\u20131215 (2008) .","journal-title":"Nature"},{"key":"BFncomms11358_CR32","doi-asserted-by":"publisher","first-page":"1019","DOI":"10.1016\/j.cell.2008.09.003","volume":"134","author":"BC Schroeder","year":"2008","unstructured":"Schroeder, B. C., Cheng, T., Jan, Y. N. & Jan, L. Y. Expression cloning of TMEM16A as a calcium-activated chloride channel subunit. Cell 134, 1019\u20131029 (2008) .","journal-title":"Cell"},{"key":"BFncomms11358_CR33","doi-asserted-by":"publisher","first-page":"590","DOI":"10.1126\/science.1163518","volume":"322","author":"A Caputo","year":"2008","unstructured":"Caputo, A. et al. TMEM16A, a membrane protein associated with calcium-dependent chloride channel activity. Science 322, 590\u2013594 (2008) .","journal-title":"Science"},{"key":"BFncomms11358_CR34","doi-asserted-by":"publisher","first-page":"2305","DOI":"10.1113\/jphysiol.2010.189506","volume":"588","author":"B Manoury","year":"2010","unstructured":"Manoury, B., Tamuleviciute, A. & Tammaro, P. TMEM16A\/anoctamin 1 protein mediates calcium-activated chloride currents in pulmonary arterial smooth muscle cells. J. Physiol. 588, 2305\u20132314 (2010) .","journal-title":"J. Physiol."},{"key":"BFncomms11358_CR35","doi-asserted-by":"publisher","first-page":"6809","DOI":"10.1523\/JNEUROSCI.5546-08.2009","volume":"29","author":"H Stohr","year":"2009","unstructured":"Stohr, H. et al. TMEM16B, a novel protein with calcium-dependent chloride channel activity, associates with a presynaptic protein complex in photoreceptor terminals. J. Neurosci. 29, 6809\u20136818 (2009) .","journal-title":"J. Neurosci."},{"key":"BFncomms11358_CR36","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1016\/j.ydbio.2008.06.009","volume":"321","author":"JR Rock","year":"2008","unstructured":"Rock, J. R., Futtner, C. R. & Harfe, B. D. The transmembrane protein TMEM16A is required for normal development of the murine trachea. Dev. Biol. 321, 141\u2013149 (2008) .","journal-title":"Dev. Biol."},{"key":"BFncomms11358_CR37","doi-asserted-by":"publisher","first-page":"374","DOI":"10.1164\/rccm.201207-1303OC","volume":"187","author":"CH Zhang","year":"2013","unstructured":"Zhang, C. H. et al. The transmembrane protein 16A Ca2+-activated Cl- channel in airway smooth muscle contributes to airway hyperresponsiveness. Am. J. Respir. Crit. Care Med. 187, 374\u2013381 (2013) .","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"BFncomms11358_CR38","doi-asserted-by":"publisher","first-page":"675","DOI":"10.1172\/JCI70025","volume":"124","author":"C Heinze","year":"2014","unstructured":"Heinze, C. et al. Disruption of vascular Ca2+-activated chloride currents lowers blood pressure. J. Clin. Invest. 124, 675\u2013686 (2014) .","journal-title":"J. Clin. Invest."},{"key":"BFncomms11358_CR39","doi-asserted-by":"publisher","first-page":"1391","DOI":"10.1007\/s00424-013-1382-1","volume":"466","author":"VS Dam","year":"2014","unstructured":"Dam, V. S., Boedtkjer, D. M., Nyvad, J., Aalkjaer, C. & Matchkov, V. TMEM16A knockdown abrogates two different Ca2+-activated Cl\u2212 currents and contractility of smooth muscle in rat mesenteric small arteries. Pflug. Arch. 466, 1391\u20131409 (2014) .","journal-title":"Pflug. Arch."},{"key":"BFncomms11358_CR40","doi-asserted-by":"publisher","first-page":"1027","DOI":"10.1161\/CIRCRESAHA.112.277145","volume":"111","author":"S Bulley","year":"2012","unstructured":"Bulley, S. et al. TMEM16A\/ANO1 channels contribute to the myogenic response in cerebral arteries. Circ. Res. 111, 1027\u20131036 (2012) .","journal-title":"Circ. Res."},{"key":"BFncomms11358_CR41","doi-asserted-by":"publisher","first-page":"10376","DOI":"10.1073\/pnas.1200174109","volume":"109","author":"P Perez-Cornejo","year":"2012","unstructured":"Perez-Cornejo, P. et al. Anoctamin 1 (Tmem16A) Ca2+-activated chloride channel stoichiometrically interacts with an ezrin-radixin-moesin network. Proc. Natl Acad. Sci. USA 109, 10376\u201310381 (2012) .","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"BFncomms11358_CR42","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1085\/jgp.200609507","volume":"128","author":"JE Angermann","year":"2006","unstructured":"Angermann, J. E., Sanguinetti, A. R., Kenyon, J. L., Leblanc, N. & Greenwood, I. A. Mechanism of the inhibition of Ca2+-activated Cl- currents by phosphorylation in pulmonary arterial smooth muscle cells. J. Gen. Physiol. 128, 73\u201387 (2006) .","journal-title":"J. Gen. Physiol."},{"key":"BFncomms11358_CR43","doi-asserted-by":"publisher","first-page":"C977","DOI":"10.1152\/ajpcell.1993.264.4.C977","volume":"264","author":"AP Morris","year":"1993","unstructured":"Morris, A. P. & Frizzell, R. A. Ca2+-dependent Cl- channels in undifferentiated human colonic cells (HT-29). II. Regulation and rundown. Am. J. Physiol. Cell Physiol. 264, C977\u2013C985 (1993) .","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"BFncomms11358_CR44","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1085\/jgp.200709933","volume":"132","author":"R Bao","year":"2008","unstructured":"Bao, R. et al. A close association of RyRs with highly dense clusters of Ca2+-activated Cl- channels underlies the activation of STICs by Ca2+ sparks in mouse airway smooth muscle. J. Gen. Physiol. 132, 145\u2013160 (2008) .","journal-title":"J. Gen. Physiol."},{"key":"BFncomms11358_CR45","doi-asserted-by":"publisher","first-page":"417","DOI":"10.1254\/jphs.FP0061332","volume":"103","author":"H Morita","year":"2007","unstructured":"Morita, H. et al. Membrane stretch-induced activation of a TRPM4-like nonselective cation channel in cerebral artery myocytes. J. Pharmacol. Sci. 103, 417\u2013426 (2007) .","journal-title":"J. Pharmacol. Sci."},{"key":"BFncomms11358_CR46","doi-asserted-by":"publisher","first-page":"653","DOI":"10.1085\/jgp.115.5.653","volume":"115","author":"M Collier","year":"2000","unstructured":"Collier, M., Ji, G., Wang, Y. X. & Kotlikoff, M. Calcium-induced calcium release in smooth muscle loose coupling between the action potential and calcium release. J. Gen. Physiol. 115, 653\u2013662 (2000) .","journal-title":"J. Gen. Physiol."},{"key":"BFncomms11358_CR47","doi-asserted-by":"publisher","first-page":"205","DOI":"10.1113\/jphysiol.2007.138982","volume":"584","author":"K Essin","year":"2007","unstructured":"Essin, K. et al. Indirect coupling between CaV1. 2 channels and ryanodine receptors to generate Ca2+ sparks in murine arterial smooth muscle cells. J. Physiol. 584, 205\u2013219 (2007) .","journal-title":"J. Physiol."},{"key":"BFncomms11358_CR48","doi-asserted-by":"publisher","first-page":"C9","DOI":"10.1152\/ajpcell.1996.271.1.C9","volume":"271","author":"A Carl","year":"1996","unstructured":"Carl, A., Lee, H. K. & Sanders, K. M. Regulation of ion channels in smooth muscles by calcium. Am. J. Physiol. Cell Physiol. 271, C9\u2013C34 (1996) .","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"BFncomms11358_CR49","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1113\/jphysiol.2002.033688","volume":"547","author":"AS Piper","year":"2003","unstructured":"Piper, A. S. & Large, W. A. Multiple conductance states of single Ca2+-activated Cl- channels in rabbit pulmonary artery smooth muscle cells. J. Physiol. 547, 181\u2013196 (2003) .","journal-title":"J. Physiol."},{"key":"BFncomms11358_CR50","doi-asserted-by":"publisher","first-page":"859","DOI":"10.1152\/physrev.00037.2013","volume":"94","author":"KM Sanders","year":"2014","unstructured":"Sanders, K. M., Ward, S. M. & Koh, S. D. Interstitial cells: regulators of smooth muscle function. Physiol. Rev. 94, 859\u2013907 (2014) .","journal-title":"Physiol. Rev."},{"key":"BFncomms11358_CR51","doi-asserted-by":"publisher","first-page":"e41","DOI":"10.1111\/j.1365-2982.2011.01806.x","volume":"24","author":"AM Duffy","year":"2012","unstructured":"Duffy, A. M., Cobine, C. A. & Keef, K. D. Changes in neuromuscular transmission in the W\/WV mouse internal anal sphincter. Neurogastroenterol. Motil. 24, e41\u2013e55 (2012) .","journal-title":"Neurogastroenterol. Motil."},{"key":"BFncomms11358_CR52","doi-asserted-by":"publisher","first-page":"1107","DOI":"10.1136\/gut.2004.051045","volume":"54","author":"F de Lorijn","year":"2005","unstructured":"de Lorijn, F. et al. Interstitial cells of Cajal are involved in the afferent limb of the rectoanal inhibitory reflex. Gut 54, 1107\u20131113 (2005) .","journal-title":"Gut"},{"key":"BFncomms11358_CR53","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1254\/jphs.14015SC","volume":"125","author":"J Ohshiro","year":"2014","unstructured":"Ohshiro, J., Yamamura, H., Suzuki, Y. & Imaizumi, Y. Modulation of TMEM16A-channel activity as Ca2+ activated Cl- conductance via the interaction with actin cytoskeleton in murine portal vein. J. Pharmacol. Sci. 125, 107\u2013111 (2014) .","journal-title":"J. Pharmacol. Sci."},{"key":"BFncomms11358_CR54","doi-asserted-by":"publisher","first-page":"G533","DOI":"10.1152\/ajpgi.2001.281.2.G533","volume":"281","author":"YF Wang","year":"2001","unstructured":"Wang, Y. F. & Daniel, E. E. Gap junctions in gastrointestinal muscle contain multiple connexins. Am. J. Physiol. Gastrointest. Liver Physiol. 281, G533\u2013G543 (2001) .","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"BFncomms11358_CR55","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1006\/exer.1996.0107","volume":"63","author":"U Samuel","year":"1996","unstructured":"Samuel, U., Lutjen-Drecoll, E. & Tamm, E. R. Gap junctions are found between iris sphincter smooth muscle cells but not in the ciliary muscle of human and monkey eyes. Exp. Eye Res. 63, 187\u2013192 (1996) .","journal-title":"Exp. Eye Res."},{"key":"BFncomms11358_CR56","doi-asserted-by":"publisher","first-page":"476","DOI":"10.1101\/gr.749203","volume":"13","author":"P Liu","year":"2003","unstructured":"Liu, P., Jenkins, N. A. & Copeland, N. G. A highly efficient recombineering-based method for generating conditional knockout mutations. Genome Res. 13, 476\u2013484 (2003) .","journal-title":"Genome Res."},{"key":"BFncomms11358_CR57","doi-asserted-by":"publisher","first-page":"845","DOI":"10.1085\/jgp.116.6.845","volume":"116","author":"R ZhuGe","year":"2000","unstructured":"ZhuGe, R. et al. Dynamics of signaling between Ca2+ sparks and Ca2+- activated K+ channels studied with a novel image-based method for direct intracellular measurement of ryanodine receptor Ca2+ current. J. Gen. Physiol. 116, 845\u2013864 (2000) .","journal-title":"J. Gen. Physiol."}],"container-title":["Nature Communications"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/ncomms11358.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/ncomms11358","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/ncomms11358.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,2]],"date-time":"2025-06-02T21:14:16Z","timestamp":1748898856000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/ncomms11358"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,4,22]]},"references-count":57,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2016,9,1]]}},"alternative-id":["BFncomms11358"],"URL":"https:\/\/doi.org\/10.1038\/ncomms11358","relation":{},"ISSN":["2041-1723"],"issn-type":[{"value":"2041-1723","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,4,22]]},"assertion":[{"value":"2 November 2015","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 March 2016","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 April 2016","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing financial interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"11358"}}