UMMS Affiliation

Department of Microbiology and Physiological Systems; Department of Medicine, Division of Cardiovascular Medicine; Program in Molecular Medicine; UMass Metabolic Network

Date

4-22-2016

Document Type

Article

Disciplines

Cellular and Molecular Physiology | Genetics | Molecular Biology | Molecular Genetics

Abstract

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.

Rights and Permissions

Citation: Nat Commun. 2016 Apr 22;7:11358. doi: 10.1038/ncomms11358. Link to article on publisher's site

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/

DOI of Published Version

10.1038/ncomms11358

Comments

Full list of authors omitted for brevity. For full list see article.

Related Resources

Link to Article in PubMed

Keywords

Cell signalling, Gastrointestinal system, Medical research

Journal Title

Nature communications

PubMed ID

27101932

Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.

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