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Nat Commun. 2016 Apr 22;7:11358. doi: 10.1038/ncomms11358.

The molecular basis of the genesis of basal tone in internal anal sphincter.

Author information

1
State Key Laboratory of Pharmaceutical Biotechnology and Model Animal Research Center and MOE Key Laboratory of Model Animal for Disease Study, Nanjing University, Nanjing 210061, China.
2
Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
3
CAM-SU Genomic Resource Center, Soochow University, Suzhou 215123, China.
4
Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA.
5
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
6
Innovation Center for Cardiovascular Disorders, Beijing 100029, China.

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.

PMID:
27101932
PMCID:
PMC4844698
DOI:
10.1038/ncomms11358
[Indexed for MEDLINE]
Free PMC Article

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