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

doi:10.1088/1674-1056/ac1e0d

中国物理B ›› 2021, Vol. 30 ›› Issue (10): 108704-108704.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

收稿日期:2021-04-26 修回日期:2021-08-01 接受日期:2021-08-17 出版日期:2021-09-17 发布日期:2021-09-17
通讯作者: Hong Qi, Jian-Wei Shuai E-mail:hongqi@sxu.edu.cn;jianweishuai@xmu.edu.cn
基金资助:
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).

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

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

Received:2021-04-26 Revised:2021-08-01 Accepted:2021-08-17 Online:2021-09-17 Published:2021-09-17
Contact: Hong Qi, Jian-Wei Shuai E-mail:hongqi@sxu.edu.cn;jianweishuai@xmu.edu.cn
Supported by:
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).

1. 2021-108704-SI.pdf(152KB)

摘要/Abstract

摘要： 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.

关键词: Ca²⁺, Bcl-2, bifurcation analysis, oscillations

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.

Key words: Ca²⁺, Bcl-2, bifurcation analysis, oscillations

中图分类号: (Ion channels)

87.16.Vy

87.17.Aa (Modeling, computer simulation of cell processes) 87.18.Vf (Systems biology)

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[J]. 中国物理B, 2021, 30(10): 108704-108704.

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

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

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