Plasma Membrane Depolarization without Repolarization Is an Early Molecular Event in Anti-Fas-induced Apoptosis

Abstract

The movement of intracellular monovalent cations has previously been shown to play a critical role in events leading to the characteristics associated with apoptosis. A loss of intracellular potassium and sodium occurs during apoptotic cell shrinkage establishing an intracellular environment favorable for nuclease activity and caspase activation. We have now investigated the potential movement of monovalent ions in Jurkat cells that occur prior to cell shrinkage following the induction of apoptosis. A rapid increase in intracellular sodium occurs early after apoptotic stimuli suggesting that the normal negative plasma membrane potential may change during cell death. We report here that diverse apoptotic stimuli caused a rapid cellular depolarization of Jurkat T-cells that occurs prior to and after cell shrinkage. In addition to the early increase in intracellular Na+, 86Rb+studies reveal a rapid inhibition of K+ uptake in response to anti-Fas. These effects on Na+ and K+ ions were accounted for by the inactivation of the Na+/K+-ATPase protein and its activity. Furthermore, ouabain, a cardiac glycoside inhibitor of the Na+/K+-ATPase, potentiated anti-Fas-induced apoptosis. Finally, activation of an anti-apoptotic signal,i.e. protein kinase C, prevented both cellular depolarization in response to anti-Fas and all downstream characteristics associated with apoptosis. Thus cellular depolarization is an important early event in anti-Fas-induced apoptosis, and the inability of cells to repolarize via inhibition of the Na+/K+-ATPase is a likely regulatory component of the death process. The movement of intracellular monovalent cations has previously been shown to play a critical role in events leading to the characteristics associated with apoptosis. A loss of intracellular potassium and sodium occurs during apoptotic cell shrinkage establishing an intracellular environment favorable for nuclease activity and caspase activation. We have now investigated the potential movement of monovalent ions in Jurkat cells that occur prior to cell shrinkage following the induction of apoptosis. A rapid increase in intracellular sodium occurs early after apoptotic stimuli suggesting that the normal negative plasma membrane potential may change during cell death. We report here that diverse apoptotic stimuli caused a rapid cellular depolarization of Jurkat T-cells that occurs prior to and after cell shrinkage. In addition to the early increase in intracellular Na+, 86Rb+studies reveal a rapid inhibition of K+ uptake in response to anti-Fas. These effects on Na+ and K+ ions were accounted for by the inactivation of the Na+/K+-ATPase protein and its activity. Furthermore, ouabain, a cardiac glycoside inhibitor of the Na+/K+-ATPase, potentiated anti-Fas-induced apoptosis. Finally, activation of an anti-apoptotic signal,i.e. protein kinase C, prevented both cellular depolarization in response to anti-Fas and all downstream characteristics associated with apoptosis. Thus cellular depolarization is an important early event in anti-Fas-induced apoptosis, and the inability of cells to repolarize via inhibition of the Na+/K+-ATPase is a likely regulatory component of the death process. plasma membrane potential protein kinase C phorbol 12-myristate 13-acetate carbonyl cyanide m-chlorophenylhydrazone bis-(1,3-dibutylbarbituric acid) trimethine oxonol 3,3′-dihexyloxacarbocyanine iodide sodium-binding benzofuran isophthalate acetyloxymethylester propidium iodide phosphate-buffered saline Tris-buffered saline mitochondrial membrane potential Apoptosis is a fundamental physiological process where activation of specific biochemical and morphological events results in cellular suicide. Although programmed cell death is a normal physiologic process observed during development and cellular homeostasis, insufficient or excessive apoptosis can lead to various pathological conditions, such as Alzheimer's and Parkinson's disease, cancer, and AIDS. The loss of cell volume, chromatin condensation, and internucleosomal DNA fragmentation are all defining characteristics of this mode of cell death. Recently, a loss of intracellular monovalent ions has been shown to play a pivotal role in apoptosis (1Wang L. Xu D. Lu L. J. Biol. Chem. 1999; 274: 3678-3685Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar, 2Yu S.P. Yeh C.-H. Strasser M. Tian M. Choi D.W. Science. 1999; 284: 336-339Crossref PubMed Scopus (210) Google Scholar, 3Dallaporta B. Hirsch T. Susin S.A. Zamzami N. Larochette N. Brenner C. Marzo I. Kroemer G. J. Immunol. 1998; 160: 5605-5615PubMed Google Scholar, 4Bilney A.J. Murray A.W. 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Palmer M. Bhakdi S. Infect. Immun. 1994; 62: 1304-1312Crossref PubMed Google Scholar). A major loss of both intracellular potassium and sodium occurs when apoptotic cells shrink and prior to the loss of membrane integrity (6Bortner C.D. Hughes Jr., F.M. Cidlowski J.A. J. Biol. Chem. 1997; 272: 32436-32442Abstract Full Text Full Text PDF PubMed Scopus (509) Google Scholar, 7Hughes Jr., F.M. Bortner C.D. Purdy G.D. Cidlowski J.A. J. Biol. Chem. 1997; 272: 30567-30576Abstract Full Text Full Text PDF PubMed Scopus (429) Google Scholar). Maintenance of the normal physiologic intracellular concentration of these monovalent ions was also shown to inhibit the activation of effector caspases (caspase-3-like enzymes) and the apoptotic nuclease activity during cell death, suggesting that the role ions play during apoptosis is more extensive than simply facilitating the loss of cell volume (7Hughes Jr., F.M. Bortner C.D. Purdy G.D. Cidlowski J.A. J. Biol. Chem. 1997; 272: 30567-30576Abstract Full Text Full Text PDF PubMed Scopus (429) Google Scholar). In most excitable cells, cellular depolarization occurs as a result of a movement of sodium ions, which can occur through a variety of mechanisms including opening of voltage-gated sodium channels (12Kallen R.G. Cohen S.A. Barchi R.L. Mol. Neurobiol. 1993; 7: 383-428Crossref PubMed Scopus (73) Google Scholar), suppression of the Na+/K+-ATPase activity (13Jones G.S. Van Dyke K. Castranova V. J. Cell. Physiol. 1981; 106: 75-83Crossref PubMed Scopus (40) Google Scholar,14Geck P. Pietrzyk C. Burckhardt B.C. Pfeiffer B. Heinz E. Biochim. Biophys. Acta. 1980; 600: 432-447Crossref PubMed Scopus (337) Google Scholar), and activation of Na+-dependent amino acid co-transport systems, which can act like sodium ionophores (15Hacking C. Eddy A. Biochem. J. 1981; 194: 415-426Crossref PubMed Scopus (16) Google Scholar, 16Philo R.D. Eddy A. Biochem. J. 1978; 174: 801-810Crossref PubMed Scopus (47) Google Scholar). In contrast to excitable cells, lymphocytes have a relatively stable sodium concentration, and very little detail is known about the movement of sodium ions in these cells, although several studies have suggested that in sodium in lymphocytes may occur by mechanisms as in cell N. J. Physiol. PubMed Google Scholar, F. J. Cell. Physiol. 1993; PubMed Scopus Google Scholar). the movement of ions, in lymphocytes likely to in a change in plasma membrane potential The loss of the mitochondrial membrane potential has been shown to occur in a variety of apoptotic M. T. J. T. K. Cell 1997; PubMed Scopus Google Scholar, N. P. M. Hirsch T. Susin S.A. B. Kroemer G. FEBS Lett. PubMed Scopus Google Scholar, A. G. E. F. S. M. D. L. D. C. Exp. Cell Res. 1994; PubMed Scopus Google Scholar). depolarization is to occur through the opening of on the mitochondrial the potential by the of ions the membrane T. S.P. Brenner B. Biochim. Biophys. Acta. 1998; PubMed Scopus Google Scholar, P. Biochim. Biophys. Acta. PubMed Scopus Google Scholar, N. P. M. C. Kroemer G. J. Exp. 1995; PubMed Scopus Google Scholar, G. Zamzami N. B. J. 1995; PubMed Scopus Google Scholar, M. I. Biochim. Biophys. Acta. 1995; PubMed Scopus Google Scholar). has shown that in the mitochondrial membrane with several characteristics of apoptosis, to to the of cells C.D. Cidlowski J.A. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). These to an early of monovalent ions, prior to the loss of cell volume, the activation of apoptosis and lead to the downstream movement of ions and apoptotic events associated with cell death. cell death characteristics to the cell and has been an in the of apoptosis. We have this to an early movement of monovalent ions occurs during apoptosis. a that in intracellular that an early increase in intracellular sodium occurs prior to the loss of cell We that this increase in intracellular sodium in in the plasma membrane and a that to in the plasma membrane potential that cells very early during apoptosis, prior to a loss in cell volume, and in response to various apoptotic We also observed that in with a of cells with intracellular K+ uptake studies suggested the rapid inactivation of the Na+/K+-ATPase, which was by a activity and We also that inhibition of the Na+/K+-ATPase by cellular depolarization and apoptosis, with an anti-apoptotic anti-Fas-induced cellular depolarization and cell death. These studies that an early movement of monovalent ions, results in plasma membrane depolarization that may movement of ions during apoptosis. Jurkat cells, were in and of apoptosis in Jurkat cells cells was or or The cells were for the The inhibitor was and the carbonyl cyanide m-chlorophenylhydrazone were 12-myristate 13-acetate of was Cell and in the of the cell were by as previously a C.D. Cidlowski J.A. J. Physiol. PubMed Google Scholar). cells were by the cells with a and on a in the is to cell a is to cell or Google Scholar). as a cell or cell volume, a in the of is with a change in A on the of the cells was on to the normal and apoptotic of cells and the in the plasma membrane potential were by was in to the potassium were by the and in and The normal and in are and for these potassium the concentration was or the concentration was such that the monovalent concentration several of the was to a concentration of Jurkat cells were in of the various potassium or in normal a of cells were for and were by a with a and was cells were and all were Jurkat cells with of an anti-Fas or were of and was in prior to of or was to of cells a concentration of and was were as in plasma membrane potential by a or as cells were and all were Jurkat cells with of an anti-Fas or were prior to of was to of cells a concentration of and was prior to propidium iodide was to a concentration of cells were by of the cells and and a and Jurkat cells cells with were in normal and a cell of cells was to a concentration of and all were of cells were for and of the was to The was in and in the and were in and the in the is shown uptake was to Jurkat cells cells in the or of of an anti-Fas were of cells were for The were in and in and in and the in the is shown The DNA for was as previously by C.D. Cidlowski J.A. J. Physiol. PubMed Google Scholar). of cells were the and by the addition of to a volume of The volume of was to with and the cells were the cells were in phosphate-buffered saline and in of in for cells were by a by on an to cell and cell The of DNA was by the of cells with DNA by the of cells The of the Na+/K+-ATPase was by the uptake of in were in the or of of an anti-Fas for prior to the was to the in the of cells for were with and in K+ of of cell were to on for and with The was in of Cell were for by in an activity is as of uptake cells in Jurkat cells were in the or of of an anti-Fas the and in for were by the cells in a and a of and and were with a of in a the was and for protein concentration by the of the of protein in and for were by for The were to for and with to the and of protein prior to were in Tris-buffered saline and and and were in and were with the for were with and for with in with were with to and The of a of intracellular and ions is for cell in this can a cell to or to cell death. We have previously shown that a loss of intracellular ions, sodium and is associated with the shrinkage of cells during apoptosis, the intracellular environment and nuclease activity and effector caspase activation (6Bortner C.D. Hughes Jr., F.M. Cidlowski J.A. J. Biol. Chem. 1997; 272: 32436-32442Abstract Full Text Full Text PDF PubMed Scopus (509) Google Scholar, 7Hughes Jr., F.M. Bortner C.D. Purdy G.D. Cidlowski J.A. J. Biol. Chem. 1997; 272: 30567-30576Abstract Full Text Full Text PDF PubMed Scopus (429) Google Scholar). In this were in a change in monovalent cations in response to apoptotic prior to cell shrinkage. Jurkat cells with anti-Fas for in intracellular sodium the sodium-binding (6Bortner C.D. Hughes Jr., F.M. Cidlowski J.A. J. Biol. Chem. 1997; 272: 32436-32442Abstract Full Text Full Text PDF PubMed Scopus (509) Google Scholar). of Jurkat cells with an anti-Fas a increase in a of cells that an increase in intracellular which prior to the loss of membrane integrity to change in intracellular potassium in these cells that this increase in intracellular sodium may in a change in the plasma membrane We the plasma to apoptotic cells for in the cell by is an that with an increase in membrane We the of this membrane potential in Jurkat by cells for in Jurkat cell were with of In the of these Jurkat cells with a increase in cellular depolarization the of this to specific to the the response of to in the mitochondrial membrane potential by various of the to the membrane potential of these We have previously shown that the of in this were in the when a mitochondrial membrane specific or a which to both in the mitochondrial and plasma membrane were to in the C.D. Cidlowski J.A. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). In contrast to the results shown for plasma membrane to in the mitochondrial membrane potential a of to in the in the occur during apoptosis, Jurkat cells were with an anti-Fas the or all known apoptotic that in mode of cell death activation C.D. Cidlowski J.A. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). apoptotic a of cells with an increase in plasma membrane was observed in a the observed cellular depolarization was a as occur in excitable cells, was as the of cells with cellular depolarization that apoptotic the of cells to repolarize is a of depolarization the cell death process. In addition to the of this cellular depolarization observed during cell death, that this event was also to the concentration of apoptotic of anti-Fas to Jurkat cells prior to in the of in a increase in the of cells with that cellular depolarization is to the of apoptotic The of plasma membrane depolarization is and after with anti-Fas of to in the plasma membrane potential of anti-Fas after Jurkat cells with or anti-Fas were for this was to of cells to a concentration of and was for an an increase in cellular depolarization in a The the results of a of Jurkat cells with anti-Fas in the of a increase in the of The the results of characteristics of apoptosis such as in the mitochondrial membrane the loss of intracellular ions, effector caspase and DNA have been shown to to the of cells (6Bortner C.D. Hughes Jr., F.M. Cidlowski J.A. J. Biol. Chem. 1997; 272: 32436-32442Abstract Full Text Full Text PDF PubMed Scopus (509) Google Scholar, 7Hughes Jr., F.M. Bortner C.D. Purdy G.D. Cidlowski J.A. J. Biol. Chem. 1997; 272: 30567-30576Abstract Full Text Full Text PDF PubMed Scopus (429) Google Scholar, C.D. Cidlowski J.A. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, C.D. Cidlowski J.A. J. Physiol. PubMed Google Scholar). cellular depolarization was also to the apoptotic cells or prior to the loss of cell which the of cellular characteristics the cell was to the cellular depolarization and cell by and the of the Jurkat cells were on a in the of a major of cells was observed on this of cells, these cells on a a of these Jurkat cells a of In on the of cells with a in in the cells with a cell that the cells an increase in or a plasma membrane of Jurkat cells with an anti-Fas in an increase in the of cells to the which apoptotic cells, the anti-Fas-induced apoptotic cells an increase in suggesting that the cells to repolarize during the cell death process. on the normal or cells in cell on a a of and a an increase in These that cellular depolarization occurs in the normal of cells, prior to the loss of cell volume, and is after cell shrinkage. In of cellular depolarization and intracellular sodium early during the apoptotic to these events were and that these are when in the response of a membrane potential in to in the is a that has been shown to to in both the plasma and mitochondrial membrane potential by a loss of membrane depolarization C.D. Cidlowski J.A. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). We have previously shown that in the the of Jurkat cells with apoptotic in this are to the of cells C.D. Cidlowski J.A. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). by to the normal and of cells, can this to in the by on the normal or in Jurkat cells with an anti-Fas or a of this in a plasma membrane depolarization with this of the normal or Jurkat cells a variety of apoptotic stimuli in an increase in a in intracellular sodium prior to the loss of cell volume of these normal or cells in the of a in suggesting cellular depolarization prior to cell shrinkage of with that cells that were a in intracellular sodium suggesting that apoptotic depolarization and intracellular sodium are is important to that and are and when these in cells have an concentration of Na+ and plasma membrane which to the cellular negative membrane of the normal or of cells with various apoptotic to reveal change in the concentration of intracellular potassium prior to the loss of cell volume previously that a in intracellular potassium occurs with cell shrinkage during apoptosis (6Bortner C.D. Hughes Jr., F.M. Cidlowski J.A. J. Biol. Chem. 1997; 272: 32436-32442Abstract Full Text Full Text PDF PubMed Scopus (509) Google Scholar, 7Hughes Jr., F.M. Bortner C.D. Purdy G.D. Cidlowski J.A. J. Biol. Chem. 1997; 272: 30567-30576Abstract Full Text Full Text PDF PubMed Scopus (429) Google Scholar). We to on anti-Fas-induced apoptosis to its in the normal physiological of cells and the to in intracellular potassium occur early in the cell death as a for K+ P. K. B.C. K. J. Biol. Chem. Full Text PDF PubMed Google in Jurkat cells with an anti-Fas In anti-Fas Jurkat cells a which as early as after apoptotic that a major in the normal the plasma membrane occurs early in the cell death process. of a the plasma membrane is for cellular and is by the plasma membrane Na+/K+-ATPase, the role of the Na+/K+-ATPase during anti-Fas-induced apoptosis. this Jurkat cells in the or of the cardiac glycoside ouabain, a known inhibitor of the Na+/K+-ATPase, for in the cell and DNA by of Jurkat cells with in a loss of in the of cells, suggesting that inhibition of the Na+/K+-ATPase cellular depolarization this cellular depolarization apoptosis, although the of in Jurkat cells with anti-Fas also in a loss in in the of cells, potentiated the of DNA with or anti-Fas which was also in the in cell The of cellular depolarization in the of a major of DNA that is by a of apoptosis is for cell death. these inhibitor the of the Na+/K+-ATPase during apoptosis a uptake of Biochim. Biophys. Acta. 1998; PubMed Scopus Google Scholar, N. J. Physiol. PubMed Google Scholar, K. J. Biol. Chem. Full Text PDF PubMed Google Scholar). uptake with the that was were in both and Jurkat cells The these for the Na+/K+-ATPase activity. shown in anti-Fas of Jurkat cells in an in Na+/K+-ATPase activity with of both the and of the Na+/K+-ATPase during anti-Fas-induced apoptosis a rapid in both the and of the also the of the with results on the uptake of during anti-Fas-induced cell death the in protein and the of of the Na+/K+-ATPase as early as after apoptotic suggesting that the Na+/K+-ATPase is a specific for inactivation during anti-Fas-induced of the Na+/K+-ATPase in the or of anti-Fas The of the Na+/K+-ATPase was by the uptake of in were in the or of of an anti-Fas prior to the was in the in the of cells for were with and in K+ of of cell were to on for and with The was in of Cell were for by in an activity is as of uptake cells in are the of a in the and of the of the Na+/K+-ATPase during anti-Fas-induced apoptosis. Jurkat cells were in the or of of an anti-Fas the and in for were and on a The were to and for the of the or of the was to and of protein prior the early in the of the Na+/K+-ATPase was observed with the specific of the of the of and Jurkat cells that the in the of the Na+/K+-ATPase in the of C, of activation during anti-Fas-induced apoptosis. Jurkat cells were with anti-Fas and for as of occurs by of the of and was by the of the were of anti-Fas is of a change in the Na+/K+-ATPase was associated with the of cells, and Jurkat cells by of the of the Na+/K+-ATPase a in the of this protein in the cells, with the cells suggesting that the loss of Na+/K+-ATPase and is to the apoptotic the activation of the and the as shown for the of the These that in Jurkat cells of the and of the of the Na+/K+-ATPase occur prior to of caspase In cell death, both plasma membrane depolarization and intracellular sodium are prevented in the of the inhibitor or the inhibitor cells a plasma membrane suggesting that more than likely to the of the C. D. and J. A. these that the Na+/K+-ATPase a role in the early movement of monovalent ions during anti-Fas-induced apoptosis by to an early change in We have shown that is anti-apoptotic in Jurkat cells and a during anti-Fas-induced cell death a of M. Bortner C.D. Cidlowski J.A. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). cell shrinkage and loss of intracellular potassium were both in the of the phorbol an of all downstream characteristics of apoptosis were also a of on cell death M. Bortner C.D. Cidlowski J.A. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). We now also prevented in the as observed during anti-Fas-induced apoptosis. Jurkat cells with anti-Fas cellular the loss of cell volume, and the increase in DNA in a of the the of this on cell or the of DNA Jurkat cells were in the of for in cell and DNA a inhibition of the apoptotic process was observed inhibition both early apoptotic events such as cellular with apoptotic characteristics such as DNA and cell suggesting that of cellular depolarization can the apoptotic process and by its to inhibit apoptosis. In this that an early increase in intracellular sodium by a variety of apoptotic stimuli is associated with plasma membrane depolarization and occurs prior the loss of cell Although in the have been previously suggested during cell death C. C. M. G. A. Exp. Cell Res. 1999; PubMed Scopus Google Scholar, D. S. K. J. Cell Biol. 1997; PubMed Scopus Google Scholar, K. A. Exp. Cell Res. 1993; PubMed Scopus Google Scholar), here report the that cellular depolarization with an early increase in intracellular sodium apoptotic that cellular depolarization is a event during apoptosis is the early activation of the cell death that cells that are prevented to a normal We have also observed plasma membrane depolarization and intracellular sodium in a variety of cells including and cells to apoptosis with or D. M. and J. A. observed plasma membrane depolarization in cells apoptosis. These that cellular depolarization is a component of the apoptotic process in both and We also that a associated with this early change in intracellular ions is the Na+/K+-ATPase, inhibition to apoptotic depolarization and of the cells to We have in and J. A. Furthermore, activation of which has previously been shown to inhibit anti-Fas-induced apoptosis, also prevented cellular a critical role of the in cell death. The of to the activation of cells has been previously C. S. J. Exp. 160: PubMed Scopus Google Scholar, S. PubMed Scopus Google Scholar). such as and a to by In protein and are also by potassium the physiological of in activation. an early increase in intracellular cellular with inhibition of the Na+/K+-ATPase during apoptosis the of the of a of the of depolarization and cell death studies that may both potassium and uptake and that inhibition of activity the loss of intracellular potassium and apoptosis M. Bortner C.D. Cidlowski J.A. J. Biol. Chem. 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