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 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.
Highlights
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
By directly examining Ca2 þ signals and ion channel activity, we further find that Ca2 þ -releasing ryanodine receptors/channels (RyRs), TMEM16A Ca2 þ -activated Cl À (ClCa) channels and L-type voltage-dependent Ca2 þ channels (VDCCs) form a module which generates a global rise in Ca2 þ, and that pharmacologically altering any one of the three channels can severely impair internal anal sphincter (IAS) basal tone
Our results demonstrate that myosin light-chain kinases (MLCK) activation by a RyR-TMEM16A ClCa channel-L-type VDCC signalling cascade in the IAS-SMCs is required for basal tone formation and maintenance, and is essential for faecal continence
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. MLCK activation in IAS-SMCs caused by a global rise in [Ca2 þ ]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. By directly examining Ca2 þ signals and ion channel activity, we further find that Ca2 þ -releasing ryanodine receptors/channels (RyRs), TMEM16A Ca2 þ -activated Cl À (ClCa) channels and L-type voltage-dependent Ca2 þ channels (VDCCs) form a module which generates a global rise in Ca2 þ , and that pharmacologically altering any one of the three channels can severely impair IAS basal tone (to the same degree as MLCK deletion). Our results demonstrate that MLCK activation by a RyR-TMEM16A ClCa channel-L-type VDCC signalling cascade in the IAS-SMCs is required for basal tone formation and maintenance, and is essential for faecal continence
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