Potential Roles of Electrogenic Ion Transport and Plasma Membrane Depolarization in Apoptosis

Abstract

Apoptosis is characterized by the programmed activation of specific biochemical pathways leading to the organized demise of cells. To date, aspects of the intracellular signaling machinery involved in this phenomenon have been extensively dissected and characterized. However, recent studies have elucidated a novel role for changes in the intracellular milieu of the cells as important modulators of the cell death program. Specially, intracellular ionic homeostasis has been reported to be a determinant in both the activation and progression of the apoptotic cascade. Several apoptotic insults trigger specific changes in ionic gradients across the plasma membrane leading to depolarization of the plasma membrane potential (PMP). These changes lead to ionic imbalance early during apoptosis. Several studies have also suggested the activation and/or modulation of specific ionic transport mechanisms including ion channels, transporters and ATPases, as mediators of altered intracellular ionic homeostasis leading to PMP depolarization during apoptosis. However, the role of PMP depolarization and of the changes in ionic homeostasis during the progression of apoptosis are still unclear. This review summarizes the current knowledge regarding the causes and consequences of PMP depolarization during apoptosis. We also review the potential electrogenic ion transport mechanisms associated with this event, including the net influx/efflux of cations and anions. An understanding of these mechamisms could lead to the generation of new therapeutic approaches for a variety of diseases involving apoptosis.

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

“…24 The inhibition of this pump makes a large contribution to plasma membrane depolarization. 25 Regulation of this pump occurs at several levels: (1) the long-term regulation, relevant to the de novo synthesis of this pump as suggested in our previous work; 16,26 (2) the short-term regulation by recruitment/internalization of the active pumps to/from the plasma membrane and modulation of ATPase activity, which is essentially involved under a variety of physiological or pathological conditions, such as sodium reabsorption in kidney. 27 This short-term regulation facilitates cells to promptly respond to the acute changes in intracellular ion environment.…”

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

“…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.…”

The SCN9A channel and plasma membrane depolarization promote cellular senescence through Rb pathway

“…This plasma membrane depolarization was then shown to mediate senescence, as (i) its reversal by knocking down SCN9A allows to bypass OIS and (ii) forced plasma membrane depolarization induces a premature senescence. It appears that plasma membrane depolarization and SCN9A have so far never been linked to cellular senescence, although it is well established that they impact cell behavior (Chifflet & Hernandez, 2012; Dib‐Hajj, Yang Black & Waxman, 2013; Franco, Bortner & Cidlowski, 2006; Suzuki‐Karasaki, Suzuki‐Karasaki, Uchida & Ochiai, 2014; Willenborg et al., 2011). …”