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

From the Gla domain to a novel small-molecule detector of apoptosis

“…A dose-dependent competitive inhibition of 3 H-ML-10 uptake was observed, attaining statistical significance at 0.2 mM concentration of the non-labeled compound, and reaching 50% inhibition at 1.36 mM. Taken together, these findings suggest membrane depolarization as a potential driving force for the observed selective uptake of Apoptosis is characterized by permanent PMD, without subsequent repolarization [17]. This clearly distinguishes the PMD observed in the apoptotic cell from physiological PMD, which normally occurs, for example, in excitable cells such as neurons or myocytes, and which is very short (millisecond range) and transient, with prompt return to baseline levels.…”

“…Even excitable tissues, such as muscle fibers or neurons, are characterized by a very short depolarization in the millisecond range, with prompt return to resting potential. In contrast, apoptosis is associated with permanent loss of these vital regulatory functions [17,19,28]. The observed selectiv- ity of ML-10 accumulation in the apoptotic cells can therefore be attributed, at least in part, to detection by the probe of this permanent and irreversible complex of apoptosis-related cellular alterations.…”

“…Such plasma membrane depolarization (PMD) without repolarization has been described as an early molecular event in Anti-Fasinduced apoptosis [17]. We therefore investigated a possible relationship between PMD and cellular uptake of 3 H-ML-10.…”

Impairment of Na+,K+-ATPase in CD95(APO-1)-induced human T-cell leukemia cell apoptosis mediated by glutathione depletion and generation of hydrogen peroxide

“…For example, ouabain was able to dramatically enhance anti-Fas-induced Jurkat cell apoptosis. 6 As a matter of fact, this enhancing effect of cardiac glycosides on CD95(APO-1)-mediated cell apoptosis can also give clues to the therapy of many immunological diseases.…”

Apoptotic volume decrease and the incredible shrinking cell

“…Recently, Na + /K + -ATPase inhibition was shown to occur during both anti-Fas and glucocorticoid induced apoptosis of lymphoid cells. 11,12 Additionally, to maintain electroneutrality, the loss of anions, particularly chloride should accompany the loss of potassium. Several recent studies have suggested that the anionic pathway triggered during AVD may be similar to that observed during an RVD response, supporting the notion of an active RVD response during apoptosis.…”