Apoptotic insults impair Na+, K+-ATPase activity as a mechanism of neuronal death mediated by concurrent ATP deficiency and oxidant stress

Abstract

The Na+, K+-ATPase (Na+,K+-pump) plays critical roles in maintaining ion homeostasis. Blocking the Na+, K+-pump may lead to apoptosis. By contrast, whether an apoptotic insult may affect the Na+,K+-pump activity is largely undefined. In cultured cortical neurons, the Na+, K+-pump activity measured as a membrane current Ipump was time-dependently suppressed by apoptotic insults including serum deprivation, staurosporine, and C2-ceramide, concomitant with depletion of intracellular ATP and production of reactive oxygen species. Signifying a putative relationship among these events, Ipump was highly sensitive to changes in ATP and reactive oxygen species levels. Moreover, the apoptosis-associated Na+, K+-pump failure and serum deprivation-induced neuronal death were antagonized by pyruvate and succinate in ATP- and reactive-oxygen-species-dependent manners. We suggest that failure of the Na+, K+-pump as a result of a combination of energy deficiency and production of reactive oxygen species is a common event in the apoptotic cascade; preserving the pump activity provides a neuroprotective strategy in certain pathological conditions.

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

“…29 Na þ ,K þ -ATPase is sensitive to ROS insult, thus has been repeatedly reported to lose its activity under oxidative stress. 17,[30][31][32] However, among a variety of biological events, generation of ROS is often useful and necessary for appropriate signal transduction. For instance, ROS were critically involved in p38 mitogen-activated protein kinase activation in angiotensin II-mediated vascular smooth muscle cell hypertrophy.…”

“…17 In brief, cells before or after treatment were collected and lysed, equal amounts of protein (500 mg) from supernatants were incubated overnight at 41C with 5 mg anti-phosphor-serine antibody (Cell signaling, Danvers, MA, USA). Antibody was subsequently bound to a saturating amount of protein A-Sepharose beads at 41C for 3-5 h. Centrifugation (5000 r.p.m.)…”

Stress-induced Expression of the γ Subunit (FXYD2) Modulates Na,K-ATPase Activity and Cell Growth

“…It also affects mitochondrial metabolism (55), with consequent inhibition of substrate oxidation, reduction in respiration, and decrease in the cellular ATP/ADP ratio. In this case, activation of Na,K-ATPase (the major energy consumer in a cell) would exacerbate an energy crisis and would be threatening for cell survival, whereas inhibition of the pump activity would be beneficial for overcoming the apoptotic insult (56). Interestingly, inhibition of Na,K-ATPase by ouabain is known to delay the development of apoptosis (57,58).…”

Neuropathology in Drosophila Mutants With Increased Seizure Susceptibility

“…It has also been suggested that cellular ATP levels are a determinant for apoptosis (Richter et al 1996), most likely through the Na 1 /K 1 ATPase (Wang et al 2003). Furthermore, insufficient Na 1 /K 1 ATPase activity to maintain ionic balances in response to episodes of ischemia, hypoglycemia, and epilepsy contributes to the neuropathy observed in those disorders (Lees 1991).…”