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The molecular basis of the genesis of basal tone in internal anal sphincter.
Zhang, Cheng-Hai; Wang, Pei; Liu, Dong-Hai; Chen, Cai-Ping; Zhao, Wei; Chen, Xin; Chen, Chen; He, Wei-Qi; Qiao, Yan-Ning; Tao, Tao; Sun, Jie; Peng, Ya-Jing; Lu, Ping; Zheng, Kaizhi; Craige, Siobhan M; Lifshitz, Lawrence M; Keaney, John F; Fogarty, Kevin E; ZhuGe, Ronghua; Zhu, Min-Sheng.
Afiliação
  • Zhang CH; 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.
  • Wang P; Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
  • Liu DH; 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.
  • Chen CP; Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
  • Zhao W; 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.
  • Chen X; 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.
  • Chen C; 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.
  • He WQ; 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.
  • Qiao YN; 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.
  • Tao T; CAM-SU Genomic Resource Center, Soochow University, Suzhou 215123, China.
  • Sun J; 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.
  • Peng YJ; 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.
  • Lu P; 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.
  • Zheng K; 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.
  • Craige SM; Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
  • Lifshitz LM; Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
  • Keaney JF; Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA.
  • Fogarty KE; Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
  • ZhuGe R; Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA.
  • Zhu MS; Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
Nat Commun ; 7: 11358, 2016 Apr 22.
Article em En | MEDLINE | ID: mdl-27101932
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.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Canal Anal / Quinase de Cadeia Leve de Miosina / Canais de Cloreto / Canal de Liberação de Cálcio do Receptor de Rianodina / Canais de Cálcio Tipo L / Incontinência Fecal / Hipotonia Muscular Idioma: En Ano de publicação: 2016 Tipo de documento: Article
Texto completo
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PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Canal Anal / Quinase de Cadeia Leve de Miosina / Canais de Cloreto / Canal de Liberação de Cálcio do Receptor de Rianodina / Canais de Cálcio Tipo L / Incontinência Fecal / Hipotonia Muscular Idioma: En Ano de publicação: 2016 Tipo de documento: Article