Bcl-2蛋白抑制钙信号的建模与全局动力学分析

钙离子(Ca~(2+))是生物体内一种"生死攸关"的信号分子,Bcl-2蛋白可以直接或间接调节IP_3R通道释放Ca~(2+)的能力,借此决定细胞命运.本文基于新近的实验成果,针对Bcl-2蛋白间接调控Ca~(2+)的信号通路建立数学模型,得到了与实验数据相符合的结果,从理论上证明了Bcl-2蛋白对钙信号有抑制作用.在对模型进行鲁棒性检验之后,本文对该信号通路中一些关键组分的作用进行了预测.以IP_3]和Bcl-2]为双分岔参数分析的结果表明Bcl-2对刺激强度能产生Ca~(2+)振荡的区域有重要影响.以蛋白磷酸酶1PP1]和蛋白激酶APKA]为单分岔参数分析的结果揭示:PP1可以有效地抑制钙信号,而PKA对钙信号的促进作用有一定的局限性.模型结果表明,不同浓度组合的IP_3,Bcl-2和PKA会对钙信号发挥复杂的调控作用.本文不仅对相关生物学实验有一定的指导作用,而且可为治疗因钙信号失调而导致的疾病提供思路.

Modeling of Bcl-2 protein suppressed calcium signaling and its global dynamics analysis

Calcium ion (Ca²⁺) is a signal for both life and death in cells. Either directly or indirectly, Bcl-2 protein can regulate Ca²⁺ release from IP₃R channel, thereby determining the cell fate. In this work, based on recent experimental results, a mathematical model is constructed to describe the signaling pathway of Ca²⁺ release regulated by Bcl-2 indirectly. The model output fits nicely to the experimental data. The model demonstrates that Bcl-2 can suppress Ca²⁺ signaling. After the robustness test of the model, the roles of some key components in the signaling pathway are predicted. Two-parameter bifurcation analyses ofIP₃] and Bcl-2] are conducted to show that Bcl-2 has a crucial role in the oscillatory region of Ca²⁺ signaling. Single-parameter bifurcation analyses of PP1] and PKA] reveal that the PP1 can inhibit Ca²⁺ from signaling potently, while PKA only promotes Ca²⁺ signaling to some extent. Our model also indicates that the different combinations of concentrations of IP₃, Bcl-2 and PKA generate complex regulations on Ca²⁺ signaling. This work not only plays a guiding role in relevant biological experiments, but also provides some insights into the treatment of diseases caused by disruption of Ca²⁺ homeostasis.