The relative contributions of store‐operated and voltage‐gated Ca ²⁺ channels to the control of Ca ²⁺ oscillations in airway smooth muscle

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.