Please wait a minute...
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

[1] Berridge M J, Bootman M D and Roderick H L 2003 Nat. Rev. Mol. Cell Biol. 4 517
[2] Orrenius S, Zhivotovsky B and Nicotera P 2003 Nat. Rev. Mol. Cell Biol. 4 552
[3] Qi H, Li X, Jin Z, Simmen T and Shuai J 2020 iScience 23 101671
[4] Chong S J F, Marchi S, Petroni G, Kroemer G, Galluzzi L and Pervaiz S 2020 Trends Cell Biol. 30 537
[5] Distelhorst C W 2018 BBA-Mol. Cell Res. 1865 1795
[6] Bezprozvanny I, Watras J and Ehrlich B E 1991 Nature 351 751
[7] Alzayady K J, Wang L, Chandrasekhar R, Wagner L E, Van Petegem F and Yule D I 2016 Sci. Signal. 9 ra35
[8] Boehning D, Patterson R L, Sedaghat L, Glebova N O, Kurosaki T and Snyder S H 2003 Nat. Cell Biol. 5 1051
[9] Yin Z, Qi H, Liu L and Jin Z 2017 BioSystems 162 44
[10] Bonneau B, Prudent J, Popgeorgiev N and Gillet G 2013 BBA-Mol. Cell Res. 1833 1755
[11] Parys J B 2014 Sci. Signal. 7 pe4
[12] Rong Y, Bultynck G, Aromolaran A S, Zhong F, Parys J B, De Smedt H, Mignery G A, Roderick H L, Bootman M D and Distelhorst C W 2009 Proc. Natl. Acad. Sci. USA 106 14397
[13] Monaco G, Decrock E, Akl H, Ponsaerts R, Vervliet T, Luyten T, De Maeyer M, Missiaen L, Distelhorst C and De Smedt H 2012 Cell Death Differ. 19 295
[14] Ivanova H, Luyten T, Decrock E, Vervliet T, Leybaert L, Parys J B and Bultynck G 2017 Cell Calcium 62 41
[15] Monaco G, La Rovere R, Karamanou S, Welkenhuyzen K, Ivanova H, Vandermarliere E, Di Martile M, Del Bufalo D, De Smedt H, Parys J B, Economou A and Bultynck G 2018 FEBS J. 285 127
[16] Chang M, Zhong F, Lavik A R, Parys J B, Berridge M J and Distelhorst C W 2014 Proc. Natl. Acad. Sci. USA 111 1186
[17] Li X, Zhong J, Gao X, Wu Y, Shuai J and Qi H 2017 Chin. Phys. B 26 128703
[18] Qi H, Jiang Y, Yin Z, Jiang K, Li L and Shuai J 2018 Phys. Chem. Chem. Phys. 20 1964
[19] Qi H, Xu G, Peng X, Li X, Shuai J and Xu R 2020 Phys. Rev. E 102 062422
[20] Li X, Zhong C, Wu R, Xu X, Yang Z, Cai S, Wu X, Chen X, Yin Z, He Q, Li D, Xu F, Yan Y, Qi H, Xie C, Shuai J and Han J 2021 Protein & Cell 2021 1
[21] Niu S, Shuai J and Qi H 2017 Acta Phys. Sin. 66 238701 (in Chinese)
[22] De Young G W and Keizer J 1992 Proc. Natl. Acad. Sci. USA 89 9895
[23] Wagner L E, Li W and Yule D I 2003 J. Biol. Chem. 278 45811
[24] Tang T, Tu H, Wang Z and Bezprozvanny I 2003 J. Neurosci. 23 403
[25] Ferrell J E and Ha S H 2014 Trends Biochem. Sci. 39 496
[26] Li H, Rao A and Hogan P G 2011 Trends Cell Biol. 21 91
[27] Parys J and Bezprozvanny I 1995 Cell Calcium 18 353
[28] Svenningsson P, Nishi A, Fisone G, Girault J A, Nairn A C and Greengard P 2004 Annu. Rev. Pharmacol. Toxicol. 44 269
[29] Shin S Y, Choo S M, Kim D, Baek S J, Wolkenhauer O and Cho K H 2006 FEBS Lett. 580 5965
[30] Neves S R, Tsokas P, Sarkar A, Grace E A, Rangamani P, Taubenfeld S M, Alberini C M, Schaff J C, Blitzer R D and Moraru I I and Iyengar R 2008 Cell 133 666
[31] Tyson J J, Chen K C and Novak B 2003 Curr. Opin. Cell Biol. 15 221
[32] Shuai J, Yang D, Pearson J and Rüdiger S 2009 Chaos 19 037105
[33] Cai X, Li X, Qi H, Wei F, Chen J and Shuai J 2016 Phys. Biol. 13 056005
[34] Lindner A U, Prehn J H M and Huber H J 2013 Mol. Biosyst. 9 2359
[35] Liu Y and Zhao H 2016 Bioinformatics 32 3782
[36] Ivanova H, Vervliet T, Monaco G, Terry L E, Rosa N, Baker M R, Parys J B, Serysheva I I, Yule D I and Bultynck G 2019 CSH Perspect. Biol. 12 a035089
[37] Greenberg E F, Lavik A R and Distelhorst C W 2014 BBA-Mol. Cell Res. 1843 2205
[38] Monteith G R, Prevarskaya N and Roberts-Thomson S J 2017 Nat. Rev. Cancer 17 373
[39] Vervloessem T, Kerkhofs M, La Rovere R M, Sneyers F, Parys J B and Bultynck G 2018 Cell Calcium 70 102
[40] Singh R, Letai A and Sarosiek K 2019 Nat. Rev. Mol. Cell Biol. 20 175
[41] Yang J, Vais H, Gu W and Foskett J K 2016 Proc. Natl. Acad. Sci. USA 113 E1953
[42] Carpio M A, Means R E, Brill A L, Sainz A, Ehrlich B E and Katz S G 2021 Cell Rep. 34 108827
[1] Numerical analysis of motional mode coupling of sympathetically cooled two-ion crystals
Li-Jun Du(杜丽军), Yan-Song Meng(蒙艳松), Yu-Ling He(贺玉玲), and Jun Xie(谢军). Chin. Phys. B, 2021, 30(7): 073702.
[2] Stabilization strategy of a car-following model with multiple time delays of the drivers
Weilin Ren(任卫林), Rongjun Cheng(程荣军), and Hongxia Ge(葛红霞). Chin. Phys. B, 2021, 30(12): 120506.
[3] Second harmonic magnetoacoustic responses of magnetic nanoparticles in magnetoacoustic tomography with magnetic induction
Gepu Guo(郭各朴), Ya Gao(高雅), Yuzhi Li(李禹志), Qingyu Ma(马青玉), Juan Tu(屠娟), Dong Zhang(章东). Chin. Phys. B, 2020, 29(3): 034302.
[4] Collapses-revivals phenomena induced by weak magnetic flux in diamond chain
Na-Na Chang(常娜娜), Wen-Quan Jing(景文泉), Yu Zhang(张钰), Ai-Xia Zhang(张爱霞), Ju-Kui Xue(薛具奎), Su-Peng Kou(寇谡鹏). Chin. Phys. B, 2020, 29(1): 010306.
[5] Magnetotransport properties of graphene layers decorated with colloid quantum dots
Ri-Jia Zhu(朱日佳), Yu-Qing Huang(黄雨青), Jia-Yu Li(李佳玉), Ning Kang(康宁), Hong-Qi Xu(徐洪起). Chin. Phys. B, 2019, 28(6): 067201.
[6] Studies of flow field characteristics during the impact of a gaseous jet on liquid-water column
Jian Wang(王健), Wen-Jun Ruan(阮文俊), Hao Wang(王浩), Li-Li Zhang(张莉莉). Chin. Phys. B, 2019, 28(6): 064704.
[7] Negative differential resistance and quantum oscillations in FeSb2 with embedded antimony
Fangdong Tang(汤方栋), Qianheng Du(杜乾衡), Cedomir Petrovic, Wei Zhang(张威), Mingquan He(何明全), Liyuan Zhang(张立源). Chin. Phys. B, 2019, 28(3): 037104.
[8] Observation of oscillations in the transport for atomic layer MoS2
Xiao-Qiang Xie(解晓强), Ying-Zi Peng(彭英姿), Qi-Ye Zheng(郑奇烨), Yuan Li(李源), Ji Chen(陈吉). Chin. Phys. B, 2018, 27(2): 028103.
[9] Effect of stochastic electromagnetic disturbances on autapse neuronal systems
Liang-Hui Qu(曲良辉), Lin Du(都琳), Zi-Chen Deng(邓子辰), Zi-Lu Cao(曹子露), Hai-Wei Hu(胡海威). Chin. Phys. B, 2018, 27(11): 118707.
[10] Generation of Fabry-Pérot oscillations and Dirac state in two-dimensional topological insulators by gate voltage
Bin Xu(徐斌), Rao Li(李饶), Hua-Hua Fu(傅华华). Chin. Phys. B, 2017, 26(5): 057303.
[11] Bursting oscillations in a hydro-turbine governing system with two time scales
Qing-Shuang Han(韩青爽), Di-Yi Chen(陈帝伊), Hao Zhang(张浩). Chin. Phys. B, 2017, 26(12): 128202.
[12] Quantum oscillations and nontrivial transport in (Bi0.92In0.08)2Se3
Minhao Zhang(张敏昊), Yan Li(李焱), Fengqi Song(宋凤麒), Xuefeng Wang(王学锋), Rong Zhang(张荣). Chin. Phys. B, 2017, 26(12): 127305.
[13] Bursting phenomena as well as the bifurcation mechanism in a coupled BVP oscillator with periodic excitation
Xiaofang Zhang(张晓芳), Lei Wu(吴磊), Qinsheng Bi(毕勤胜). Chin. Phys. B, 2016, 25(7): 070501.
[14] Quantum transport properties of the three-dimensional Dirac semimetal Cd3As2 single crystals
Lan-Po He(何兰坡), Shi-Yan Li(李世燕). Chin. Phys. B, 2016, 25(11): 117105.
[15] Electric-field-dependent charge delocalization from dopant atoms in silicon junctionless nanowire transistor
Hao Wang(王昊), Wei-Hua Han(韩伟华), Xiao-Song Zhao(赵晓松), Wang Zhang(张望), Qi-Feng Lyu(吕奇峰), Liu-Hong Ma(马刘红), Fu-Hua Yang(杨富华). Chin. Phys. B, 2016, 25(10): 108102.
No Suggested Reading articles found!