Authors: 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 Jr, Kevin E. Fogarty, Ronghua ZhuGe, Min-Sheng Zhu
Summary:
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.
Source:
Nature Communications; 2016, 7: 11358