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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Anal Canal / drug effects
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Anal Canal / metabolism*
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Anal Canal / physiopathology
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Animals
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Anoctamin-1
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Bethanechol / pharmacology
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Calcium / metabolism
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Calcium Channels, L-Type / genetics
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Calcium Channels, L-Type / metabolism*
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Calcium Signaling
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Chloride Channels / genetics
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Chloride Channels / metabolism*
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Defecation / drug effects
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Fecal Incontinence / genetics
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Fecal Incontinence / metabolism*
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Fecal Incontinence / physiopathology
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Female
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Gene Expression Regulation
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Humans
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Male
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Membrane Potentials / drug effects
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Membrane Potentials / physiology
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Muscle Contraction / drug effects
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Muscle Hypotonia / genetics
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Muscle Hypotonia / metabolism*
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Muscle Hypotonia / physiopathology
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Muscle, Smooth / drug effects
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Muscle, Smooth / metabolism
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Muscle, Smooth / physiopathology
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Myosin-Light-Chain Kinase / deficiency
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Myosin-Light-Chain Kinase / genetics*
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Nifedipine / pharmacology
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Niflumic Acid / pharmacology
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Patch-Clamp Techniques
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Ryanodine Receptor Calcium Release Channel / genetics
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Ryanodine Receptor Calcium Release Channel / metabolism*
Substances
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ANO1 protein, mouse
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Anoctamin-1
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Calcium Channels, L-Type
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Chloride Channels
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Ryanodine Receptor Calcium Release Channel
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Bethanechol
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Niflumic Acid
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Myosin-Light-Chain Kinase
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Nifedipine
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Calcium