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Chin. Phys. B, 2021, Vol. 30(10): 108704    DOI: 10.1088/1674-1056/ac1e0d

Dual mechanisms of Bcl-2 regulation in IP3-receptor-mediated Ca2+ release: A computational study

Hong Qi(祁宏)1,2,†, Zhi-Qiang Shi(史志强)1,3, Zhi-Chao Li(李智超)1,3, Chang-Jun Sun(孙长君)1,3, Shi-Miao Wang(王世苗)3, Xiang Li(李翔)4,5, and Jian-Wei Shuai(帅建伟)4,5,‡
1 Complex Systems Research Center, Shanxi University, Taiyuan 030006, China;
2 Shanxi Key Laboratory of Mathematical Techniques and Big Data Analysis on Disease Control and Prevention, Shanxi University, Taiyuan 030006, China;
3 School of Mathematical Sciences, Shanxi University, Taiyuan 030006, China;
4 Department of Physics and Fujian Provincial Key Laboratory for Soft Functional Materials Research, Xiamen University, Xiamen 361005, China;
5 State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, and National Institute for Data Science in Health and Medicine, Xiamen University, Xiamen 361005, China
Abstract  Inositol 1,4,5-trisphosphate receptors (IP3R)-mediated calcium ion (Ca2+) release plays a central role in the regulation of cell survival and death. Bcl-2 limits the Ca2+ release function of the IP3R through a direct or indirect mechanism. However, the two mechanisms are overwhelmingly complex and not completely understood. Here, we convert the mechanisms into a set of ordinary differential equations. We firstly simulate the time evolution of Ca2+ concentration under two different levels of Bcl-2 for the direct and indirect mechanism models and compare them with experimental results available in the literature. Secondly, we employ one- and two-parameter bifurcation analysis to demonstrate that Bcl-2 can suppress Ca2+ signal from a global point of view both in the direct and indirect mechanism models. We then use mathematical analysis to clarify that the indirect mechanism is more efficient than the direct mechanism in repressing Ca2+ signal. Lastly, we predict that the two mechanisms restrict Ca2+ signal synergistically. Together, our study provides theoretical insights into Bcl-2 regulation in IP3R-mediated Ca2+ release, which may be instrumental for the successful development of therapies to target Bcl-2 for cancer treatment.
Keywords:  Ca2+      Bcl-2      bifurcation analysis      oscillations  
Received:  26 April 2021      Revised:  01 August 2021      Accepted manuscript online:  17 August 2021
PACS:  87.16.Vy (Ion channels)  
  87.17.Aa (Modeling, computer simulation of cell processes)  
  87.18.Vf (Systems biology)  
Fund: Project supported by Shanxi Province Science Foundation for Youths (Grant No. 201901D211159) and the National Natural Science Foundation of China (Grant Nos. 11504214, 11874310, and 12090052).
Corresponding Authors:  Hong Qi, Jian-Wei Shuai     E-mail:;

Cite this article: 

Hong Qi(祁宏), Zhi-Qiang Shi(史志强), Zhi-Chao Li(李智超), Chang-Jun Sun(孙长君), Shi-Miao Wang(王世苗), Xiang Li(李翔), and Jian-Wei Shuai(帅建伟) Dual mechanisms of Bcl-2 regulation in IP3-receptor-mediated Ca2+ release: A computational study 2021 Chin. Phys. B 30 108704

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