Activation of Store-Operated Calcium Entry in Airway Smooth Muscle Cells: Insight from a Mathematical Model

Abstract

Intracellular Ca2+ dynamics of airway smooth muscle cells (ASMC) mediate ASMC contraction and proliferation, and thus play a key role in airway hyper-responsiveness (AHR) and remodelling in asthma. We evaluate the importance of store-operated Ca2+ entry (SOCE) in these Ca2+ dynamics by constructing a mathematical model of ASMC Ca2+ signaling based on experimental data from lung slices. The model confirms that SOCE is elicited upon sufficient Ca2+ depletion of the sarcoplasmic reticulum (SR), while receptor-operated Ca2+ entry (ROCE) is inhibited in such conditions. It also shows that SOCE can sustain agonist-induced Ca2+ oscillations in the absence of other Ca2+ influx. SOCE up-regulation may thus contribute to AHR by increasing the Ca2+ oscillation frequency that in turn regulates ASMC contraction. The model also provides an explanation for the failure of the SERCA pump blocker CPA to clamp the cytosolic Ca2+ of ASMC in lung slices, by showing that CPA is unable to maintain the SR empty of Ca2+. This prediction is confirmed by experimental data from mouse lung slices, and strongly suggests that CPA only partially inhibits SERCA in ASMC. © 2013 Croisier et al.