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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 [Ca …