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

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.