Non-selective cation channels and oxidative stress-induced cell swelling

Necrosis is considered as a non-specific form of cell death that induces tissue inflammation and is preceded by cell swelling. This increase in cell volume has been ascribed mainly to defective outward pumping of Na⁺ caused by metabolic depletion and/or to increased Na⁺ influx via membrane transporters. A specific mechanism of swelling and necrosis driven by the influx of Na⁺ through nonselective cation channels has been recently proposed (Barros et al., 2001a). We have characterized further the properties of the nonselective cation channel (NSCC) in HTC cells. The NSCC shows a conductance of ∼ 18 pS, is equally permeable to Na⁺ and K⁺, impermeant to Ca²⁺, requires high intracellular Ca²⁺ as well as low intracellular ATP for activation and is inhibited by flufenamic acid. Hydrogen peroxide induced a significant increase in cell volume that was dependent on external Na⁺. We propose that the NSCC, which is ubiquitous though largely inactive in healthy cells, becomes activated under severe oxidative stress. The ensuing Na⁺ influx initiates via positive feedback a series of metabolic and electrolytic disturbances, resulting in cell death by necrosis.