摘要：SummaryAlthough a rising concentration of cytosolic Ca2+has long been recognized as an essential signal for apoptosis, the dynamical mechanisms by which Ca2+regulates apoptosis are not clear yet. To address this, we constructed a computational model that integrates known biochemical reactions and can reproduce the dynamical behaviors of Ca2+-induced apoptosis as observed in experiments. Model analysis shows that oscillating Ca2+signals first convert into gradual signals and eventually transform into a switch-like apoptotic response. Via the two processes, the apoptotic signaling pathway filters the frequency of Ca2+oscillations effectively but instead responds acutely to their amplitude. Collectively, our results suggest that Ca2+regulates apoptosis mainly via oscillation amplitude, rather than frequency, modulation. This study not only provides a comprehensive understanding of how oscillatory Ca2+dynamically regulates the complex apoptotic signaling network but also presents a typical example of how Ca2+controls cellular responses through amplitude modulation.Graphical AbstractDisplay OmittedHighlights•A signaling network of cytosolic Ca2+-induced apoptosis is constructed•The network is converted into a mathematical model composed of four modules•Oscillatory signals first transform into gradual ones and then into switch-like ones•Ca2+regulates apoptosis mainly via amplitude, rather than frequency, modulationBiological Sciences; Cell Biology; Mathematical Biosciences
