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 C, Lui D, Lu P, Zheng K, Craige SM, Lifshitz L, Keaney JF, Fogarty KE, Zhuge R, Zhu M. (2016). The molecular basis of the genesis of basal tone in internal anal sphincter. Open Access Publications by UMMS Authors. https://doi.org/10.1038/ncomms11358. Retrieved from https://escholarship.umassmed.edu/oapubs/2856
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This work is licensed under a Creative Commons Attribution 4.0 License.