gel matrix). The mathematical model establishes a closed feedback loop between the calcium system and the extracellular environment that gives rise to the self-regulation we observed. We ran extensive simulations where parameters associated with the influx and efflux of Ca 2þ were modulated such that they are either up-regulated or down-regulated by NO. In silico results are filtered out to qualitatively match cell-in-gel in vitro results. The filtering process is based on measures that capture multiple properties of calcium profiles. Conclusion: Our approach of identification hints that the upregulation of NO has the effect of simultaneously modulating multiple parameters of the Ca 2þ handling pathway. Of the modulated parameters, the L-type current amplitude has to be consistently increased. Coupled with the increase in L-type current, parameters associated with release and uptake of calcium by the SR have to be modulated in opposite directions.