Department of Microbiology and Physiological Systems; Department of Medicine, Division of Cardiovascular Medicine; Program in Molecular Medicine; UMass Metabolic Network
Cellular and Molecular Physiology | Genetics | Molecular Biology | Molecular Genetics
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.
Cell signalling, Gastrointestinal system, Medical research
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DOI of Published Version
Nat Commun. 2016 Apr 22;7:11358. doi: 10.1038/ncomms11358. Link to article on publisher's site
Zhang, Cheng-Hai; Lui, Donghai; Lu, Ping; Zheng, Kaizhi; Craige, Siobhan M.; Lifshitz, Lawrence; Keaney, John F. Jr.; Fogarty, Kevin E.; Zhuge, Ronghua; and Zhu, Min-Sheng, "The molecular basis of the genesis of basal tone in internal anal sphincter" (2016). Open Access Articles. 2856.
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.