A dynamic model of calcium signaling in mast cells and LTC4 release induced by mechanical stimuli

Abstract

Mast cells (MCs) play an important role in the immune system. It is known that mechanical stimuli can induce intracellular Ca2+ signal and release a variety of mediators, including leukotriene C4 (LTC4), leading to other cellular and physiological changes. In this paper, we present a mathematical model to explore signalling pathways in MCs, by including cellular mechanisms for intracellular $$\hbox{Ca}^{2+}$$ increase and LTC4 release in response to mechanical stimuli, thapsigargin (TG, SERCA pump inhibitor), and LTC4 stimuli. We show that (i) mechanical stimuli activate mechano-sensitive ion channels and induce inward ion fluxes and Ca2+ entry which increases intracellular Ca2+ concentration and releases LTC4; (ii) TG inhibits SERCA pumps, empties the internal Ca2+ stores, which activates Ca2+ release-activated Ca2+ channels and results in sustained intracellular Ca2+ increase; and (iii) LTC4 activates receptors on MCs surface and increases intracellular Ca2+ concentration. Our results are consistent with experimental observations, and furthermore, they also reveal that mechanical stimuli can increase intracellular Ca2+ even when LTC4 release is blocked, which suggests a feed forward loop involved in LTC4 production. This study may facilitate our understanding of the mechanotransduction process in MCs and provide a useful modeling tool for quantitatively analyzing immune mechanisms involving MCs.