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

Summary

Although a rising concentration of cytosolic Ca ²⁺ has long been recognized as an essential signal for apoptosis, the dynamical mechanisms by which Ca ²⁺ 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 ²⁺-induced apoptosis as observed in experiments. Model analysis shows that oscillating Ca ²⁺ 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 ²⁺ oscillations effectively but instead responds acutely to their amplitude. Collectively, our results suggest that Ca ²⁺ regulates apoptosis mainly via oscillation amplitude, rather than frequency, modulation. This study not only provides a comprehensive understanding of how oscillatory Ca ²⁺ dynamically regulates the complex apoptotic signaling network but also presents a typical example of how Ca ²⁺ controls cellular responses through amplitude modulation.

Graphical Abstract

Highlights

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  A signaling network of cytosolic Ca ²⁺-induced apoptosis is constructed

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  The network is converted into a mathematical model composed of four modules

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  Oscillatory signals first transform into gradual ones and then into switch-like ones

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  Ca ²⁺ regulates apoptosis mainly via amplitude, rather than frequency, modulation

Abstract

Biological Sciences; Cell Biology; Mathematical Biosciences