Skip to main content
SpringerLink
Log in

The role of apoptotic volume decrease and ionic homeostasis in the activation and repression of apoptosis

  • Invited Review
  • Published:
Pflügers Archiv Aims and scope Submit manuscript

Abstract

The mechanism of activation and repression of apoptosis has been a central focus of many studies examining the role of programmed cell death in both normal and pathological conditions. Despite intensive research efforts, the precise cellular and molecular mechanisms that trigger and/or prevent apoptosis remain undefined. A universal characteristic of apoptosis is the loss of cell volume or cell shrinkage, recently termed apoptotic volume decrease. While cell shrinkage has traditionally been viewed as a passive event during apoptosis, recent work from several laboratories has shown that the loss of cell volume, or more specifically the flux of ions associated with the change in cell size, play a critical role in the regulation of the cell death machinery. On going studies continue to support the hypothesis that the change in intracellular ions can alter a cells decision to die by apoptosis.

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

Similar content being viewed by others

References

  1. Al-Habori M (1994) Cell volume and ion transport regulation. Int J Biochem 26:319–334

    Article  CAS  PubMed  Google Scholar 

  2. Barros LF, Hermosilla T, Castro J (2001) Necrotic volume increase and the early physiology of necrosis. Comp Biochem Physiol 130:401–409

    Article  CAS  Google Scholar 

  3. Bock J, Szabó I, Jekle A, Gulbins E (2002) Actinomycin D-induced apoptosis involves the potassium channel Kv1.3. Biochem Biophys Res Commun 295:526–531

    Article  CAS  PubMed  Google Scholar 

  4. Bortner CD, Cidlowski JA (1996) Absence of volume regulatory mechanisms contributes to the rapid activation of apoptosis in thymocytes. Am J Physiol 271:C950–C961

    CAS  PubMed  Google Scholar 

  5. Bortner CD, Cidlowski JA (1998) A necessary role for cell shrinkage in apoptosis. Biochem Pharmacol 56:1549–1559

    PubMed  Google Scholar 

  6. Bortner CD, Cidlowski JA (2002) Apoptotic volume decrease and the incredible shrinkage cell. Cell Death Differ 9:1307–1310

    Article  CAS  PubMed  Google Scholar 

  7. Bortner CD, Cidlowski JA (2003) Uncoupling cell shrinkage from apoptosis reveals that Na+ influx is required for volume loss during programmed cell death. J Biol Chem 278:39176–39184

    Article  CAS  PubMed  Google Scholar 

  8. Bortner CD, Hughes FM Jr, Cidlowski JA (1997) A primary role for K+ and Na+ efflux in the activation of apoptosis. J Biol Chem 272:32436–32442

    CAS  PubMed  Google Scholar 

  9. Bortner CD, Gomez-Angelats M, Cidlowski JA (2001) Plasma membrane depolarization without repolarization is an early molecular event in anti-Fas-induced apoptosis. J Biol Chem 276:4304–4314

    Article  CAS  PubMed  Google Scholar 

  10. Cain K, Langlais C, Sun XM, Brown DG, Cohen GM (2001) Physiological concentrations of K+ inhibit cytochrome c-dependent formation of the apoptosome. J Biol Chem 276:41985–41990

    Article  CAS  PubMed  Google Scholar 

  11. Carini R, Autelli R, Bellomo G, Albano E (1999) Alterations of cell volume regulation in the development of hepatocyte necrosis. Exp Cell Res 248:280-293

    Article  PubMed  Google Scholar 

  12. Colom LV, Diaz ME, Beers DR, Neely A, Xie WJ, Appel SH (1998) Role of potassium channels in amyloid-induced cell death. J Neurochem 70:1925–1934

    CAS  PubMed  Google Scholar 

  13. Elliott JI, Higgins CF (2003) IKCa1 activity is required for cell shrinkage, phosphatidylserine translocation and death in T lymphocyte apoptosis. EMBO Rep 4:189–194

    Article  CAS  PubMed  Google Scholar 

  14. Fernandez-Segura E, Canizares FJ, Cubero MA, Warley A, Campos A (1999) Changes in elemental content during apoptotic cell death by electron probe X-ray microanalysis. Exp Cell Res 253:454–462

    Article  CAS  PubMed  Google Scholar 

  15. Hoffmann EK (1987) Volume regulation in cultured cells. Curr Top Membr Trans 30:125–180

    Google Scholar 

  16. Hughes FM Jr, Bortner CD, Purdy GD, Cidlowski JA (1997) Intracellular K+ suppresses the activation of apoptosis in lymphocytes. J Biol Chem 272:30567–30576

    Article  CAS  PubMed  Google Scholar 

  17. Jonas D, Walev I, Berger T, Liebetrau M, Palmer M, Bhakdi S (1994) Novel path to apoptosis: small transmembrane pores created by staphylococcal alpha-toxin in T lymphocytes evokes internucleosomal DNA degradation. Infect Immunol 62:1304–1312

    CAS  Google Scholar 

  18. Kerr JFR (1965) A histochemical study of hypertrophy and ischaemic injury of rat liver with special reference to changes in lysosomes. J Pathol Bacteriol 90:419–435

    CAS  PubMed  Google Scholar 

  19. Kerr JFR (1971) Shrinkage necrosis: a distinct mode of cellular death. J Pathol 105:13–20

    CAS  PubMed  Google Scholar 

  20. Krick S, Platoshyn O, McDaniel SS, Rubin LJ, Yuan JX (2001) Augmented K(+) currents and mitochondrial membrane depolarization in pulmonary artery myocyte apoptosis. Am J Physiol 281:L887–L894

    CAS  Google Scholar 

  21. Krick S, Platoshyn O, Sweeney M, Kim H, Yuan JX (2001) Activation of K+ channels induces apoptosis in vascular smooth muscle cells. Am J Physiol 280:C970–C979

    CAS  Google Scholar 

  22. Lang F, Busch GL, Ritter M, Volkl H, Waldegger S, Gulbins E, Haussinger D (1998) Functional significance of cell volume regulatory mechanisms. Physiol Rev 78:247–306

    PubMed  Google Scholar 

  23. Lang F, Ritter M, Gamper N, Huber S, Fillon S, Tanneur V, Lepple-Wienhues A, Szabo I, Gulbins E (2000) Cell volume in the regulation of cell proliferation and apoptotic cell death. Cell Physiol Biochem 10:417–428

    CAS  PubMed  Google Scholar 

  24. Leist M, Single B, Castoldi AF, Kühnle S, Nicotera P (1997) Intracellular adenosine triphosphate (ATP) concentrations: a switch in the decision between apoptosis and necrosis. J Exp Med 185:1481–1486

    CAS  PubMed  Google Scholar 

  25. Maeno E, Ishizaki Y, Kanaseki T, Hazama A, Okada Y (2000) Normotonic cell shrinkage because of disordered volume regulation is an early prerequisite to apoptosis. Proc Natl Acad Sci USA 97:9487–9492

    PubMed  Google Scholar 

  26. Okada Y, Maeno E, Shimizu T, Dezaki K, Wang J, Morishima S (2001) Receptor-mediated control of regulatory volume decrease (RVD) and apoptotic volume decrease (AVD). J Physiol 532:3–16

    CAS  PubMed  Google Scholar 

  27. Mann CL, Bortner CD, Jewell CM, Cidlowski JA (2001) Glucocorticoid-induced plasma membrane depolarization during thymocyte apoptosis: association with cell shrinkage and degradation of the Na+/K+-adenosine triphosphatase. Endocrinology 142:5059–5068

    Article  CAS  PubMed  Google Scholar 

  28. McCarthy JV, Cotter TG (1997) Cell shrinkage and apoptosis: a role for potassium and sodium ion efflux. Cell Death Differ 4:756–770

    Article  CAS  Google Scholar 

  29. McConkey DJ (1998) Biochemical determinants of apoptosis and necrosis. Toxicol Lett 99:157–168

    Article  CAS  PubMed  Google Scholar 

  30. Nieminen AL (2003) Apoptosis and necrosis in health and disease: role of mitochondria. Int Rev Cytol 224:29–55

    CAS  PubMed  Google Scholar 

  31. Nobel, CS, Aronson JK, Dobbelsteen DJ van den, Slater AF (2000) Inhibition of Na+/K+-ATPase may be one mechanism contributing to potassium efflux and cell shrinkage in CD95-induced apoptosis. Apoptosis 5:153–163

    Article  CAS  PubMed  Google Scholar 

  32. Offen D, Ziv I, Gorodin S, Barzilai A, Malik Z, Melamed E (1995) Dopamine-induced programmed cell death in mouse thymocytes. Biochem Biophys Acta 1268:171–177

    Article  CAS  PubMed  Google Scholar 

  33. Orlov SN, Pchejetski D, Taurin S, Thorin-Trescases N, Maxomov GV, Pshezhetsky AV, Rubin AB, Hamet P (2004) Apoptosis in serum-deprived vascular smooth muscle cells: evidence for cell volume-independent mechanism. Apoptosis 9:55–66

    Article  CAS  PubMed  Google Scholar 

  34. Perregaux DG, Laliberte RE, Gabel CA (1996) Human monocyte interleukin-1β posttranslational processing: evidence of a volume-regulated response. J Biol Chem 271:29830–29838

    Article  CAS  PubMed  Google Scholar 

  35. Platoshyn O, Zhang S, McDaniel SS, Yuan JX (2002) Cytochrome c activates K+ channels before inducing apoptosis. Am J Physiol 283:C1298–C1305

    CAS  Google Scholar 

  36. Skepper JN, Karydis I, Garnett MR, Hegyi L, Hardwick SJ, Warley A, Mitchinson MJ Cary NR (1999) Changes in elemental concentrations are associated with early stages of apoptosis in human monocyte-macrophages exposed to oxidized low-density lipoprotein: an X-ray microanalytical study. J Pathol 188:100–106

    Article  CAS  PubMed  Google Scholar 

  37. Small DL, Tauskela J, Xia Z (2002) Role for chloride but not potassium channels in apoptosis in primary rat cortical cultures. Neurosci Lett 334:95–98

    Article  CAS  PubMed  Google Scholar 

  38. Storey NM, Gómez-Angelats M, Bortner CD, Armstrong DL, Cidlowski JA (2003) Stimulation of Kv1.3 potassium channels by death receptors during apoptosis in Jurkat T lymphocytes. J Biol Chem 278:33319–33326

    Article  CAS  PubMed  Google Scholar 

  39. Thompson GJ, Langlais C, Cain K, Conley EC, Cohen GM (2001) Elevated extracellular [K+] inhibits death-receptor- and chemical-mediated apoptosis prior to caspase activation and cytochrome c release. Biochem J 357:137–145

    Article  CAS  PubMed  Google Scholar 

  40. Waldegger S, Lang F (1998) Cell volume and gene expression. J Membr Biol 162:95–100

    Article  CAS  PubMed  Google Scholar 

  41. Walev I, Reske K, Pamer M, Valeva A, Bhakdi S (1995) Potassium-inhibited processing of IL-1B in human monocytes. EMBO J 14:1607–1614

    CAS  PubMed  Google Scholar 

  42. Wang H, Zhang Y, Cao L, Han H, Wang J, Yang B, Nattel S, Wang Z (2002) HERG K+ channel, a regulator of tumor cell apoptosis and proliferation. Cancer Res 62:4843–4848

    CAS  PubMed  Google Scholar 

  43. Yu SP, Choi DW (2000) Ions, cell volume, and apoptosis. Proc Natl Acad Sci USA 97:9360–9362

    CAS  PubMed  Google Scholar 

  44. Yu SP, Yeh CH, Sensi SL, Gwag BJ, Canzoniero LM, Farhangrazi ZS, Ying HS, Tian M, Dugan LL, Choi DW (1997) Mediation of neuronal apoptosis by enhancement of outward potassium current. Science 278:114–117

    CAS  PubMed  Google Scholar 

  45. Yu SP, Yeh C, Strasser U, Tian M, Choi DW (1999) NMDA receptor-mediated K+ efflux and neuronal apoptosis. Science 284:336–339

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. The Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, Department of Health and Human Services, National Institutes of Health, Research Triangle Park, NC 27709, USA

    Carl D. Bortner & John A. Cidlowski

Authors
  1. Carl D. Bortner
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. John A. Cidlowski
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to John A. Cidlowski.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bortner, C.D., Cidlowski, J.A. The role of apoptotic volume decrease and ionic homeostasis in the activation and repression of apoptosis. Pflugers Arch - Eur J Physiol 448, 313–318 (2004). https://doi.org/10.1007/s00424-004-1266-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00424-004-1266-5

Keywords

Search

Navigation