The molecular basis of the genesis of basal tone in internal anal sphincter

Nat Commun. 2016 Apr 22;7:11358. doi: 10.1038/ncomms11358.

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

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anal Canal / drug effects
  • Anal Canal / metabolism*
  • Anal Canal / physiopathology
  • Animals
  • Anoctamin-1
  • Bethanechol / pharmacology
  • Caffeine / pharmacology
  • Calcium / metabolism
  • Calcium Channels, L-Type / genetics
  • Calcium Channels, L-Type / metabolism*
  • Calcium Signaling
  • Chloride Channels / genetics
  • Chloride Channels / metabolism*
  • Defecation / drug effects
  • Fecal Incontinence / genetics
  • Fecal Incontinence / metabolism*
  • Fecal Incontinence / physiopathology
  • Female
  • Gene Expression Regulation
  • Humans
  • Male
  • Membrane Potentials / drug effects
  • Membrane Potentials / physiology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Muscle Contraction / drug effects
  • Muscle Hypotonia / genetics
  • Muscle Hypotonia / metabolism*
  • Muscle Hypotonia / physiopathology
  • Muscle, Smooth / drug effects
  • Muscle, Smooth / metabolism
  • Muscle, Smooth / physiopathology
  • Myosin-Light-Chain Kinase / deficiency
  • Myosin-Light-Chain Kinase / genetics*
  • Nifedipine / pharmacology
  • Niflumic Acid / pharmacology
  • Patch-Clamp Techniques
  • Ryanodine Receptor Calcium Release Channel / genetics
  • Ryanodine Receptor Calcium Release Channel / metabolism*

Substances

  • ANO1 protein, mouse
  • Anoctamin-1
  • Calcium Channels, L-Type
  • Chloride Channels
  • Ryanodine Receptor Calcium Release Channel
  • Bethanechol
  • Caffeine
  • Niflumic Acid
  • Myosin-Light-Chain Kinase
  • Nifedipine
  • Calcium