Na(+), K(+)-ATPase: the new face of an old player in pathogenesis and apoptotic/hybrid cell death.

The Na(+), K(+)-ATPase is a ubiquitous membrane transport protein in mammalian cells, responsible for establishing and maintaining high K(+) and low Na(+) in the cytoplasm required for normal resting membrane potentials and various cellular activities. The ionic homeostasis maintained by the Na(+), K(+)-ATPase is also critical for cell growth, differentiation, and cell survival. Although the toxic effects of blocking the Na(+), K(+)-ATPase by ouabain and other selective inhibitors have been known for years, the mechanism of action remained unclear. Recent progress in two areas has significantly advanced our understanding of the role and mechanism of Na(+), K(+)-ATPase in cell death. Along with increased recognition of apoptosis in a wide range of disease states, Na(+), K(+)-ATPase deficiency has been identified as a contributor to apoptosis and pathogenesis. More importantly, accumulating evidence now endorses a close relationship between ionic homeostasis and apoptosis, namely the regulation of apoptosis by K(+) homeostasis. Since Na(+), K(+)-ATPase is the primary system for K(+) uptake, dysfunction of the transport enzyme and resultant disruption of ionic homeostasis have been re-evaluated for their critical roles in apoptosis and apoptosis-related diseases. In this review, instead of giving a detailed description of the structure and regulation of Na(+), K(+)-ATPase, the author will focus on the most recent evidence indicating the unique role of Na(+), K(+)-ATPase in cell death, including apoptosis and the newly recognized "hybrid death" of concurrent apoptosis and necrosis in the same cells. It is also hoped that discussion of some seemingly conflicting reports will inspire further debate and benefit future investigation in this important research field.