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

Intracellular [Image: see text] 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 [Image: see text] entry (SOCE) in these [Image: see text] dynamics by constructing a mathematical model of ASMC [Image: see text] signaling based on experimental data from lung slices. The model confirms that SOCE is elicited upon sufficient [Image: see text] depletion of the sarcoplasmic reticulum (SR), while receptor-operated [Image: see text] entry (ROCE) is inhibited in such conditions. It also shows that SOCE can sustain agonist-induced [Image: see text] oscillations in the absence of other [Image: see text] influx. SOCE up-regulation may thus contribute to AHR by increasing the [Image: see text] 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 [Image: see text] of ASMC in lung slices, by showing that CPA is unable to maintain the SR empty of [Image: see text]. This prediction is confirmed by experimental data from mouse lung slices, and strongly suggests that CPA only partially inhibits SERCA in ASMC.