Abstract
The spontaneous tone of the internal anal sphincter(IAS)primarily controls rectoanal continence. Multiple signal networks with or without MLCK have been implicated in IAS contractility, but the underlying regulatory mechanism and functional importance are incompletely understood. We analyzed mice with specific knockout of Mlck in adult smooth muscle and characterized in-vivo function of MLCK in IAS. Targeted deletion of Mlck in adult smooth muscle resulted in abnormal excretion. Mutant IAS displayed an abolished spontaneous tone, and impaired contractile response to KCl and bethanechol. This was compatible with reduction of RLC phosphorylation. The kinetics of force production showed that MLCK concentration in IAS was linearly correlated with basal tone, logarithmically correlated with the force induced by KCl or bethanechol. About 20% of MLCK was sufficient to produce a maximal contractile response to KCl and BCh, but a very weak spontaneous tone. This concentration dependency emphasized the importance of MLCK in IAS contractility. The differential dependency implied different activation features of MLCK during spontaneous tone formation and contractile response to stimuli. We thus concluded that MLCK and its RLC phosphorylation were required for spontaneous tone and depolarization- or agonist-induced contraction, possibly through different activation mechanisms.
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