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

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 I_pump 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, I_pump 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.