Premium
Nonselective cation channels as effectors of free radical–induced rat liver cell necrosis
Author(s) -
Barros Luis Felipe,
Stutzin Andrés,
Calixto Andrea,
Catalán Marcelo,
Castro Joel,
Hetz Claudio,
Hermosilla Tamara
Publication year - 2001
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1053/jhep.2001.20530
Subject(s) - chemistry , oxidative stress , necrosis , microbiology and biotechnology , flufenamic acid , biophysics , niflumic acid , apoptosis , programmed cell death , trpm2 , extracellular , menadione , biochemistry , transient receptor potential channel , biology , medicine , receptor
Necrosis, as opposed to apoptosis, is recognized as a nonspecific cell death that induces tissue inflammation and is preceded by cell edema. In non‐neuronal cells, the latter has been explained by defective outward pumping of Na + caused by metabolic depletion or by increased Na + influx via membrane transporters. Here we describe a novel mechanism of swelling and necrosis; namely the influx of Na + through oxidative stress‐activated nonselective cation channels. Exposure of liver epithelial Clone 9 cells to the free‐radical donors calphostin C or menadione induced the rapid activation of an approximately 16‐pS nonselective cation channel (NSCC). Blockage of this conductance with flufenamic acid protected the cells against swelling, calcium overload, and necrosis. Protection was also achieved by Gd 3+ , an inhibitor of stretch‐activated cation channels, or by isosmotic replacement of extracellular Na + with N ‐methyl‐D‐glucamine. It is proposed that NSCCs, which are ubiquitous although largely inactive in healthy cells, become activated under severe oxidative stress. The ensuing influx of Na + initiates a positive feedback of metabolic and electrolytic disturbances leading cells to their necrotic demise.