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

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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
    University of Massachusetts Medical School)

  • 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
    CAM-SU Genomic Resource Center, Soochow 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 Jr

    (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
    Innovation Center for Cardiovascular Disorders)

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.

Suggested Citation

  • 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 , 2016. "The molecular basis of the genesis of basal tone in internal anal sphincter," Nature Communications, Nature, vol. 7(1), pages 1-10, September.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms11358
    DOI: 10.1038/ncomms11358
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    Cited by:

    1. Weijia Sun & Shuai Guo & Yuheng Li & JianWei Li & Caizhi Liu & Yafei Chen & Xuzhao Wang & Yingjun Tan & Hua Tian & Cheng Wang & Ruikai Du & Guohui Zhong & Sai Shi & Biao Ma & Chang Qu & Jingxuan Fu & , 2022. "Anoctamin 1 controls bone resorption by coupling Cl− channel activation with RANKL-RANK signaling transduction," Nature Communications, Nature, vol. 13(1), pages 1-15, December.

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