The Oscillation Amplitude, Not the Frequency of Cytosolic Calcium, Regulates Apoptosis Induction.

Although a rising concentration of cytosolic Ca has long been recognized as an essential signal for apoptosis, the dynamical mechanisms by which Ca 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 Ca-induced apoptosis as observed in experiments. Model analysis shows that oscillating Ca 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 Ca oscillations effectively but instead responds acutely to their amplitude. Collectively, our results suggest that Ca regulates apoptosis mainly via oscillation amplitude, rather than frequency, modulation. This study not only provides a comprehensive understanding of how oscillatory Ca dynamically regulates the complex apoptotic signaling network but also presents a typical example of how Ca controls cellular responses through amplitude modulation.