Figure 1.

Schematic diagram of the major pathways involved in the model of Ca²⁺ dynamics in airway smooth muscle cells (ASMCs). Solid black lines denote Ca²⁺ fluxes. Stimulation of cell surface G protein–coupled receptors (GPCR) leads to production of inositol 1,4,5-triphosphate (IP₃) and activation of the IP₃ receptor (IP₃R). Subsequent release of Ca²⁺ from the sarcoplasmic reticulum (SR) leads to Ca²⁺-induced Ca²⁺ release (CICR) through either IP₃R or ryanodine receptors (RyRs). Depletion of the SR induces the opening of store-operated Ca²⁺ channels (SOCCs) in the plasma membrane but also inactivates RyR. Ca²⁺ is removed from the cytoplasm by plasma membrane ATPase (PMCA) or by sarcoplasmic/endoplasmic reticulum Ca²⁺ ATPase (SERCA). Addition of extracellular KCl leads to membrane depolarization and opening of voltage-operated Ca²⁺ channels (VOCCs). The consequent increase in Ca²⁺ influx causes (in the absence of agonist) overfilling of the SR and activation of RyR. IP₃R and RyR interact via their effects on the concentration of Ca²⁺ ([Ca²⁺]) in the cytosol and the SR. Here, we focus on the predicted effects of caffeine (and other compounds), which sensitizes RyR to cytosolic and luminal Ca²⁺.