A quantitative description of active force generation in gastrointestinal smooth muscle

A mathematical model to describe the relationship between the intracellular Ca2+ concentration and active force production in a gastrointestinal (GI) smooth muscle cell (SMC) has been developed. Here the model has been constructed in terms of two modules, the first describing the activation of myosin light chain kinase (MLCK) through its interactions with calmodulin and Ca2+ ions, and the second consisting of a four state scheme describing myosin phosphorylation and cross-bridge formation between actin and myosin. A prescribed Ca2+ transient, representing the dynamic changes in intracellular free Ca2+ that accompanies GI SMC excitation, was used as the input signal. Simulations demonstrated that at physiological Ca2+ levels, a 33% increase in peak Ca2+ concentration resulted in a 93% increase in myosin phosphorylation. This can possibly be attributed to the steep relationship between Ca2+ and MLCK activation over the normal Ca2+ range. The total number of cross-bridges (sum of cycling cross-bridges and latch-bridges) was used to predict the active force generated in response to a phasic Ca2+ signal. The predicted forces were in qualitative agreement with experimental data from a canine antral smooth muscle strip. The development of this model represents a first step towards a greater understanding of the mechanisms that underlie GI motility. Copyright (C) 2010 John Wiley & Sons, Ltd.