Skip to main content
SpringerLink
Log in

Bcl-2 Modulates Endoplasmic Reticulum and Mitochondrial Calcium Stores in PC12 Cells

  • Original Paper
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

Endoplasmic reticulum (ER) and mitochondria are intracellular organelles and their interactions are directly involved in different processes such as Ca2+ signaling in cell survival and death mechanisms. Bcl-2 is an anti-apoptotic protein intrinsically related to ER and mitochondria, modulating Ca2+ content in these organelles. We investigated the effects of Bcl-2 overexpression on ER and mitochondrial Ca2+ dynamics in PC12 cells. Bcl-2 overexpressing and control cells were loaded with Fura 2/AM and stimulated with different drugs. Results showed that in Bcl-2 cells, ACh induced a lower Ca2+ response compared to control. Ca2+ release induced by TG was decreased in Bcl-2 cells, however, it was greater in Caff induced Ca2+ rise. In addition, FCCP induced a higher Ca2+ release in Bcl-2 cells. These results suggest that Bcl-2 overexpression modulate the ER Ca2+ pools differently and the release of ER Ca2+ may increase mitochondrial Ca2+ accumulation. These alterations of intracellular Ca2+ stores are important mechanisms for the control of Ca2+ signaling.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Dong Z, Saikumar P, Weinberg JM et al (2006) Calcium in cell injury and death. Annu Rev Pathol Mech Disc 1:405–444

    Article  CAS  Google Scholar 

  2. Berridge MJ, Bootman MD, Roderick HL (2003) Calcium signaling dynamics, homeostasis and remodeling. Nat Rev Mol Cell Biol 4:517–529

    Article  PubMed  CAS  Google Scholar 

  3. Putney JW Jr (1986) A model for receptor-regulated calcium entry. Cell Calcium 7:1–12

    Article  PubMed  CAS  Google Scholar 

  4. Vaca L (2010) SOCIC: The store-operated calcium influx complex. Cell calcium 47:199–209

    Article  PubMed  CAS  Google Scholar 

  5. Rizzuto R, Bernardi P, Pozzan T (2000) Mitochondria as all-round players of the calcium game. Physiol 529:37–47

    Article  CAS  Google Scholar 

  6. Lujubicic V, Hood DA (2009) Diminished contraction-induced intracellular signaling towards mitochondrial biogenesis in aged skeletal muscle. Aging Cell 8:394–404

    Article  Google Scholar 

  7. Ureshino RP, Bertoncini CR, Fernandes MJ et al (2010) Alterations in calcium signaling and a decrease in Bcl-2 expression: possible correlation with apoptosis in aged striatum. J Neurosci Res 88:438–447

    Article  PubMed  CAS  Google Scholar 

  8. Montero M, Alonso MT, Carnicero E et al (2000) Chromaffin-cell stimulation triggers fast millimolar mitochondrial Ca2+ transients that modulate secretion. Nature Cell Biol 2:57–61

    Article  PubMed  CAS  Google Scholar 

  9. Rizzuto R, Brini M, Murgia M et al (1993) Microdomains with high Ca2 + close to IP3–sensitive channels that are sensed by neighboring mitochondria. Science 262:744–747

    Article  PubMed  CAS  Google Scholar 

  10. Rizzuto R, Pinton P, Carrington W et al (1998) Close contacts with the endoplasmic reticulum as determinants of mitochondrial Ca2+ responses. Science 280:1763–1766

    Article  PubMed  CAS  Google Scholar 

  11. Csordás G, Thomas AP, Hajnóczky G (1999) Quasi-synaptic calcium signal transmission between endoplasmic reticulum and mitochondria. EMBO J 18:96–108

    Article  PubMed  Google Scholar 

  12. Dispersyn G, Nuydens R, Connors R et al (1999) Bcl-2 protects against FCCP-induced apoptosis and mitochondrial membrane potential depolarization in PC12 cells. Biochemica Biophysica Acta 1428:357–371

    Article  CAS  Google Scholar 

  13. Lam M, Dubyak G, Chen L et al (1994) Evidence that Bcl-2 represses apoptosis by regulating endoplasmic reticulum-associated Ca2+ fluxes. PNAS 91:6569–6573

    Article  PubMed  CAS  Google Scholar 

  14. Chen R, Valencia I, Zhoong F et al (2004) Bcl-2 functionally interacts with inositol 1, 4, 5-trisphosphate receptors to regulate calcium release from the ER in response to inositol 1, 4, 5-trisphosphate. J Cell Biol 166:193–203

    Article  PubMed  CAS  Google Scholar 

  15. Xu L, Kong D, Zhu L et al (2007) Suppression of IP3-mediated calcium release and apoptosis by Bcl-2 involves the participation of protein phosphatase 1. Mol Cell Biochem 295:153–165

    Article  PubMed  CAS  Google Scholar 

  16. Rong YP, Bultynck G, Aromolaran AS et al (2009) The BH4 domain of Bcl-2 inhibits ER calcium release and apoptosis by binding the regulatory and coupling domain of the IP3 receptor. Proc Natl Acad Sci 106:14397–14402

    Article  PubMed  CAS  Google Scholar 

  17. Abeele FV, Skryma R, Shuba Y et al (2002) Bcl-2-dependent modulation of Ca2+ homeostasis and store-operated channels in prostate cancer cells. Cancer Cell 1:169–179

    Article  Google Scholar 

  18. Palmer AE, Can Jin, Reed JC et al (2004) Bcl-2-mediated alterations in edoplasmic reticulum Ca2+ analyzed with an improved genetically encoded fluorescent sensor. PNAS 101:17404–17409

    Article  PubMed  CAS  Google Scholar 

  19. Zhu L, Ling S, Yu XD et al (1999) Modulation of mitochondrial Ca2+ homeostasis by Bcl-2. J BiolChem 274:33267–33273

    CAS  Google Scholar 

  20. Murphy AN, Bredesen DE, Cortopassi G et al (1996) Bcl-2 potentiates the maximal calcium uptake capacity of neural cell mitochondria. PNAS 93:9893–9898

    Article  PubMed  CAS  Google Scholar 

  21. White C, Chi L, Yang J (2005) The edoplasmic reticulum gateway to apoptosis by Bcl-XL modulation of the InsP3R. Nat Cell Biol 7:1021–1028

    Article  PubMed  CAS  Google Scholar 

  22. Pinton P, Ferrari D, Magalhães P et al (2000) Reduced loading of intracellular Ca2+ stores and downregulation of capacitative Ca2+ influx in Bcl-2-overexpressing cells. JCell Biol 148:857–862

    Article  CAS  Google Scholar 

  23. Foyouzi-Youssefi R, Arnaudeau S, Borner C et al (2000) Bcl-2 decreases the free Ca2+ concentration within the endoplasmic reticulum. PNAS 97:5723–5728

    Article  PubMed  CAS  Google Scholar 

  24. Smaili SS, Russell JT (1999) Permeability transition pore regulates both mitochondrial membrane potential and agonist-evoked Ca2+ signals in oligodendrocyte progenitors. Cell calcium 26:121–130

    Article  PubMed  CAS  Google Scholar 

  25. Budd SL, Nicholls DG (1996) A reevaluation of the role of mitochondria in neuronal Ca2+ homeostasis. J Neurochem 66:403–411

    Article  PubMed  CAS  Google Scholar 

  26. He H, Lam M, McCormick TS et al (1997) Maintenance of calcium homeostasis in the endoplasmic reticulum by Bcl-2. JCell Biol 138:1219–1228

    Article  CAS  Google Scholar 

  27. Zhang QH, Sheng HP, Loh TT (2001) Bcl-2 protects HL-60 cells from apoptosis by stabilizing their intracellular calcium “pool”s. Life Sciences 68:2873–2883

    Article  PubMed  CAS  Google Scholar 

  28. Ferrari D, Pinton P, Szabadadkai G et al (2002) Endoplasmic reticulum, Bcl-2 and Ca2+ handling in apoptosis. Cell Calcium 32:413–420

    Article  PubMed  CAS  Google Scholar 

  29. Wei H, Wei W, Bredesen DE (1998) Bcl-2 protects against apoptosis in neuronal cell line caused by thapsigargin-induced depletion of intracellular calcium stores. J Neurochem 70:2305–2314

    Article  PubMed  CAS  Google Scholar 

  30. Kuo TH, H-RCh Kim, Zhu L et al (1998) Modulation of endoplasmic reticulum calcium pump by Bcl-2. Oncogene 17:1903–1910

    Article  PubMed  CAS  Google Scholar 

  31. Granville DJ, Ruehlmann DO, Cjoy JC et al (2001) Bcl-2 increases emptying of endoplasmic reticulum Ca2+ stores during photodynamic therapy-induced apoptosis. Cell Calcium 30:343–350

    Article  PubMed  CAS  Google Scholar 

  32. Distelhorst CW and Bootman MD (2011) Bcl-2 interaction with the inositol 1,4,5-trisphosphate receptor: role in Ca2 + signaling and disease. Cell Calcium epub May 29

  33. Vicencio JM, Ortiz C, Criollo A, Jones AW, Kepp O, Galluzzi L, Joza N, Vitale I, Morselli E, Tailler M, Castedo M, Maiuri MC, Molgó J, Szabadkai G, Lavandero S, Kroemer G (2009) The inositol 1, 4, 5-trisphosphate regulates autophagy through its interaction with Beclin 1. Cell Death and Diff 16:1006–1017

    Article  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP). Conselho Nacional de Pesquisas (CNPq) and Coordenação Aperfeiçoamento de Pessoal de Nivel Superior (CAPES). Thanks are due to Paul Anderson for his assistance with the imaging system and BioIP software and to Cícero R. dos Santos and Maria de Lourdes L. dos Santos for their technical support.

Author information

Authors and Affiliations

  1. Departamento de Farmacologia, Universidade Federal de São Paulo (UNIFESP/EPM), Rua Três de Maio 100, São Paulo-SP, CEO: 04044-020, Brazil

    Hanako Hirata, Guiomar S. Lopes, Aron Jurkiewicz, Lucia Garcez-do-Carmo & Soraya S. Smaili

Authors
  1. Hanako Hirata
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Guiomar S. Lopes
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Aron Jurkiewicz
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lucia Garcez-do-Carmo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Soraya S. Smaili
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Soraya S. Smaili.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hirata, H., Lopes, G.S., Jurkiewicz, A. et al. Bcl-2 Modulates Endoplasmic Reticulum and Mitochondrial Calcium Stores in PC12 Cells. Neurochem Res 37, 238–243 (2012). https://doi.org/10.1007/s11064-011-0600-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-011-0600-5

Keywords

Search

Navigation