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

Cheng-Hai Zhang, Pei Wang, Dong-Hai Liu, Cai-Ping Chen, Wei Zhao, Xin Chen, Chen Chen, Wei-Qi He, Yan-Ning Qiao, Tao Tao, Jie Sun, Ya-Jing Peng, Ping Lu, Kaizhi Zheng, Siobhan M. Craige, Lawrence M. Lifshitz, John F. Keaney, Kevin E. Fogarty, Ronghua ZhuGe () and Min-Sheng Zhu ()
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Cheng-Hai Zhang: State Key Laboratory of Pharmaceutical Biotechnology and Model Animal Research Center and MOE Key Laboratory of Model Animal for Disease Study, Nanjing University
Pei Wang: State Key Laboratory of Pharmaceutical Biotechnology and Model Animal Research Center and MOE Key Laboratory of Model Animal for Disease Study, Nanjing University
Dong-Hai Liu: University of Massachusetts Medical School
Cai-Ping Chen: State Key Laboratory of Pharmaceutical Biotechnology and Model Animal Research Center and MOE Key Laboratory of Model Animal for Disease Study, Nanjing University
Wei Zhao: State Key Laboratory of Pharmaceutical Biotechnology and Model Animal Research Center and MOE Key Laboratory of Model Animal for Disease Study, Nanjing University
Xin Chen: State Key Laboratory of Pharmaceutical Biotechnology and Model Animal Research Center and MOE Key Laboratory of Model Animal for Disease Study, Nanjing University
Chen Chen: State Key Laboratory of Pharmaceutical Biotechnology and Model Animal Research Center and MOE Key Laboratory of Model Animal for Disease Study, Nanjing University
Wei-Qi He: State Key Laboratory of Pharmaceutical Biotechnology and Model Animal Research Center and MOE Key Laboratory of Model Animal for Disease Study, Nanjing University
Yan-Ning Qiao: State Key Laboratory of Pharmaceutical Biotechnology and Model Animal Research Center and MOE Key Laboratory of Model Animal for Disease Study, Nanjing University
Tao Tao: State Key Laboratory of Pharmaceutical Biotechnology and Model Animal Research Center and MOE Key Laboratory of Model Animal for Disease Study, Nanjing University
Jie Sun: State Key Laboratory of Pharmaceutical Biotechnology and Model Animal Research Center and MOE Key Laboratory of Model Animal for Disease Study, Nanjing University
Ya-Jing Peng: State Key Laboratory of Pharmaceutical Biotechnology and Model Animal Research Center and MOE Key Laboratory of Model Animal for Disease Study, Nanjing University
Ping Lu: University of Massachusetts Medical School
Kaizhi Zheng: University of Massachusetts Medical School
Siobhan M. Craige: University of Massachusetts Medical School
Lawrence M. Lifshitz: Program in Molecular Medicine, University of Massachusetts Medical School
John F. Keaney: University of Massachusetts Medical School
Kevin E. Fogarty: Program in Molecular Medicine, University of Massachusetts Medical School
Ronghua ZhuGe: University of Massachusetts Medical School
Min-Sheng Zhu: State Key Laboratory of Pharmaceutical Biotechnology and Model Animal Research Center and MOE Key Laboratory of Model Animal for Disease Study, Nanjing University

Nature Communications, 2016, vol. 7, issue 1, 1-10

Abstract: 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 Ca2+ channels (VDCCs) or TMEM16A Ca2+-activated Cl− channels significantly changes global cytosolic Ca2+ concentration ([Ca2+]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 [Ca2+]i and impairs the tone and defecation. Hence, MLCK activation in IAS-SMCs caused by a global rise in [Ca2+]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.

Date: 2016
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DOI: 10.1038/ncomms11358

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