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 approximately 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.
Simon
Felipe
F
Laboratorio de Fisiopatología Molecular, Programa de Fisiopatología, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Independencia 1027, Santiago, Chile.
Varela
Diego
D
Riveros
Ana
A
Eguiguren
Ana Luisa
AL
Stutzin
Andres
A
D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D016923:Cell Death / Q000502:physiology*; D048429:Cell Size / Q000502:physiology*; D005439:Flufenamic Acid / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007473:Ion Channels / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress; D051381:Rats; D012964:Sodium / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000894:Anti-Inflammatory Agents, Non-Steroidal; D007473:Ion Channels; D016877:Oxidants; C491711:nonselective cation channel protein, rat; D005439:Flufenamic Acid; D000255:Adenosine Triphosphate; D012964:Sodium; D006861:Hydrogen Peroxide