Ryanodine Receptor Sensitization Results in Abnormal Calcium Signaling in Airway Smooth Muscle Cells

Intracellular Ca2+ dynamics of airway smooth muscle cells (ASMCs) are believed to play a major role in airway hyperresponsiveness and remodeling in asthma. Prior studies have underscored a prominent role for inositol 1,4,5-triphosphate (IP3) receptors in normal agonist-induced Ca2+ oscillations, whereas ryanodine receptors (RyRs) appear to remain closed during such Ca2+ oscillations, which mediate ASMC contraction. Nevertheless, RyRs have been hypothesized to play a role in hyperresponsive Ca2+ signaling. This could be explained by RyRs being “sensitized” to open more frequently by certain compounds. We investigate the implications of RyR sensitization on Ca2+ dynamics in ASMC using a combination of mathematical modeling and experiments with mouse precision-cut lung slices. Caffeine is used to increase the sensitivity of RyRs to cytosolic Ca2+ concentration ([Ca2+]i) and sarcoplasmic reticulum Ca2+ ([Ca2+]SR). In ASMCs, high caffeine concentrations (>10 mM) induce a sustained elevation of [Ca2+]i. Our mat...