Regulators of Calcium Homeostasis Identified by Inference of Kinetic Model Parameters from Live Single Cells Perturbed by siRNA

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Sci. Signal.  09 Jul 2013:
Vol. 6, Issue 283, pp. ra56
DOI: 10.1126/scisignal.2003649

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Computing Regulatory Functions

Complex regulatory networks can be constructed without a complete understanding of the functions of each of the components. Bandara et al. illustrate how differential equations modeling and parameter estimation from experiments with live single cells can reveal protein function. They applied their computational approach to the analysis of the effects of small interfering RNAs targeting components of the calcium homeostasis network, which involves various channels, calcium sensors, and transporters in the endoplasmic reticulum and plasma membrane. This approach properly identified known functions of network components and revealed previously unknown mechanisms involved in regulating calcium homeostasis. In addition, both presenilin-2, a protein associated with Alzheimer’s disease, and ORAI2, a channel previously only implicated in store-operated calcium entry, were implicated in mediating calcium leak from the endoplasmic reticulum.