Mathematical modeling of mechanisms underlying ACh-induced [Ca²⁺]_i oscillations in tracheal smooth muscle

In porcine tracheal smooth muscle (TSM) cells, ACh induces [Ca²⁺]_i oscillations, which reflect Ca²⁺ release through ryanodine receptor (RyR) channels in the sarcoplasmic reticulum (SR). These ACh-induced [Ca²⁺]_i oscillations display an initial period of faster oscillations followed by a slower steady state phase. This biphasic pattern may reflect either the dynamic release kinetics of RyR channels (one-compartment model) or the interactive influence of RyR mediated Ca²⁺ release and other Ca²⁺ regulatory mechanisms (two-compartment model). These alternative models were simulated under 2 experimental conditions: 1) intact TSM cells, where all Ca²⁺ regulatory mechanisms were present, and 2) β-escin permeabilized cells where the influence of Ca²⁺ influx and efflux was eliminated. Initial model parameters were constrained based on previously reported values. We found that a two-compartment model best fits the biphasic pattern of ACh-induced [Ca²⁺]_i oscillations in intact TSM cells, consistent with the involvement of more than RyR channels. When the influence of Ca²⁺ influx and efflux were removed in β-escin permeabilized TSM cells, ACh-induced [Ca²⁺]_i oscillations could be modeled by one-compartment. Similarly, a one-compartment model adequately represented the steady state phase of ACh-induced [Ca²⁺]_i oscillations. We conclude that dynamic modulation of ACh-induced [Ca²⁺]_i oscillations involves Ca²⁺ regulatory mechanisms other than RyR mediated Ca²⁺ release.