The relative contributions of store-operated and voltage-gated Ca2+ channels to the control of Ca2+ oscillations in airway smooth muscle.

KEY POINTS: Agonist-dependent oscillations in the concentration of free cytosolic calcium are a vital mechanism for the control of airway smooth muscle contraction and thus are a critical factor in airway hyper-responsiveness. Using a mathematical model, closely tied to experimental work, we show that the oscillations in membrane potential accompanying the calcium oscillations have no significant effect on the properties of the calcium oscillations. In addition, the model shows that calcium entry through store-operated calcium channels is critical for calcium oscillations, but calcium entry through voltage-gated channels has much less effect. The model predicts that voltage-gated channels are less important than store-operated channels in the control of airway smooth muscle tone. ABSTRACT: Airway smooth muscle contraction is typically the key mechanism underlying airway hyper-responsiveness, and the strength of muscle contraction is determined by the frequency of oscillations of intracellular calcium (Ca2+ ) concentration. In airway smooth muscle cells, these Ca2+ oscillations are caused by cyclic Ca2+ release from the sarcoplasmic reticulum, although Ca2+ influx via plasma membrane channels is also necessary to sustain the oscillations over longer times. To assess the relative contributions of store-operated and voltage-gated Ca2+ channels to this Ca2+ influx, we generated a comprehensive mathematical model, based on experimental Ca2+ measurements in mouse precision-cut lung slices, to simulate Ca2+ oscillations and changes in membrane potential. Agonist-induced Ca2+ oscillations are accompanied by oscillations in membrane potential, although the membrane potential oscillations are too small to generate large Ca2+ currents through voltage-gated Ca2+ channels, and thus have little effect on the Ca2+ oscillations. Ca2+ entry through voltage-gated channels only becomes important when the cell is depolarized (e.g. by a high external K+ concentration). As a result, agonist-induced Ca2+ oscillations are critically dependent on Ca2+ entry through store-operated channels but do not depend strongly on Ca2+ entry though voltage-gated channels.