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dc.contributor.authorZhang, Cheng-Hai
dc.contributor.authorLui, Donghai
dc.contributor.authorLu, Ping
dc.contributor.authorZheng, Kaizhi
dc.contributor.authorCraige, Siobhan M.
dc.contributor.authorLifshitz, Lawrence
dc.contributor.authorKeaney, John F. Jr.
dc.contributor.authorFogarty, Kevin E.
dc.contributor.authorZhuge, Ronghua
dc.contributor.authorZhu, Min-Sheng
dc.date2022-08-11T08:09:45.000
dc.date.accessioned2022-08-23T16:42:14Z
dc.date.available2022-08-23T16:42:14Z
dc.date.issued2016-04-22
dc.date.submitted2016-08-16
dc.identifier.citationNat Commun. 2016 Apr 22;7:11358. doi: 10.1038/ncomms11358. <a href="http://dx.doi.org/10.1038/ncomms11358">Link to article on publisher's site</a>
dc.identifier.issn2041-1723 (Linking)
dc.identifier.doi10.1038/ncomms11358
dc.identifier.pmid27101932
dc.identifier.urihttp://hdl.handle.net/20.500.14038/40051
dc.description<p>Full list of authors omitted for brevity. For full list see article.</p>
dc.description.abstractSmooth 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(2+) channels (VDCCs) or TMEM16A Ca(2+)-activated Cl(-) channels significantly changes global cytosolic Ca(2+) concentration ([Ca(2+)]i) 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(2+)]i and impairs the tone and defecation. Hence, MLCK activation in IAS-SMCs caused by a global rise in [Ca(2+)]i via a RyR-TMEM16A-VDCC signalling module sets the basal tone. Targeting this module may lead to new treatments for diseases like faecal incontinence.
dc.language.isoen_US
dc.relation<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=27101932&dopt=Abstract">Link to Article in PubMed</a>
dc.rightsThis work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectCell signalling
dc.subjectGastrointestinal system
dc.subjectMedical research
dc.subjectCellular and Molecular Physiology
dc.subjectGenetics
dc.subjectMolecular Biology
dc.subjectMolecular Genetics
dc.titleThe molecular basis of the genesis of basal tone in internal anal sphincter
dc.typeJournal Article
dc.source.journaltitleNature communications
dc.source.volume7
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=3861&amp;context=oapubs&amp;unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/oapubs/2856
dc.identifier.contextkey8985405
refterms.dateFOA2022-08-23T16:42:14Z
html.description.abstract<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(2+) channels (VDCCs) or TMEM16A Ca(2+)-activated Cl(-) channels significantly changes global cytosolic Ca(2+) concentration ([Ca(2+)]i) 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(2+)]i and impairs the tone and defecation. Hence, MLCK activation in IAS-SMCs caused by a global rise in [Ca(2+)]i via a RyR-TMEM16A-VDCC signalling module sets the basal tone. Targeting this module may lead to new treatments for diseases like faecal incontinence.</p>
dc.identifier.submissionpathoapubs/2856
dc.contributor.departmentUMass Metabolic Network
dc.contributor.departmentProgram in Molecular Medicine
dc.contributor.departmentDepartment of Medicine, Division of Cardiovascular Medicine
dc.contributor.departmentDepartment of Microbiology and Physiological Systems
dc.source.pages11358


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This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
Except where otherwise noted, this item's license is described as This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/