Abstract
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 (Ca(2+) ) concentration. In airway smooth muscle cells, these Ca(2+) oscillations are caused by cyclic Ca(2+) release from the sarcoplasmic reticulum, although Ca(2+) 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 Ca(2+) channels to this Ca(2+) influx, we generated a comprehensive mathematical model, based on experimental Ca(2+) measurements in mouse precision-cut lung slices, to simulate Ca(2+) oscillations and changes in membrane potential. Agonist-induced Ca(2+) oscillations are accompanied by oscillations in membrane potential, although the membrane potential oscillations are too small to generate large Ca(2+) currents through voltage-gated Ca(2+) channels, and thus have little effect on the Ca(2+) oscillations. Ca(2+) 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 Ca(2+) oscillations are critically dependent on Ca(2+) entry through store-operated channels but do not depend strongly on Ca(2+) entry though voltage-gated channels.