Nonselective cation channels as effectors of free radical-induced rat liver cell necrosis.
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.
Barros
L F
LF
Instituto de Ciencias Biomédicas Facultad de Medicina, Universidad de Chile, Santiago, Chile. fbarros@cecs.cl
Stutzin
A
A
Calixto
A
A
Catalán
M
M
Castro
J
J
Hetz
C
C
Hermosilla
T
T
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002412:Cations / Q000378:metabolism*; D002478:Cells, Cultured; D004553:Electric Conductivity; D005110:Extracellular Space / Q000378:metabolism; D005609:Free Radicals / Q000378:metabolism*; D005682:Gadolinium / Q000494:pharmacology; D007473:Ion Channels / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000502:physiology*; D008099:Liver / Q000473:pathology* / Q000503:physiopathology; D008536:Meglumine / Q000378:metabolism; D009281:Naphthalenes / Q000494:pharmacology; D009336:Necrosis; D018384:Oxidative Stress / Q000502:physiology; D051381:Rats; D012964:Sodium / Q000378:metabolism; D014812:Vitamin K / Q000494:pharmacology; D062367:ortho-Aminobenzoates / Q000494:pharmacology
D002121:Calcium Channel Blockers; D002412:Cations; D005609:Free Radicals; D007473:Ion Channels; D009281:Naphthalenes; D062367:ortho-Aminobenzoates; D014812:Vitamin K; D008536:Meglumine; C001209:fenamic acid; D012964:Sodium; D005682:Gadolinium; C058819:calphostin C; D002118:Calcium