Involvement of ceramide in hyperosmotic shock-induced death of erythrocytes.
Erythrocytes lack nuclei and mitochondria, the organelles important for apoptosis of nucleated cells. However, following increase of cytosolic Ca(2+) activity, erythrocytes undergo cell shrinkage, cell membrane blebbing and breakdown of phosphatidylserine asymmetry, all features typical for apoptosis in nucleated cells. The same events are observed following osmotic shock, an effect mediated in part by activation of Ca(2+)-permeable cation channels. However, erythrocyte death following osmotic shock is blunted but not prevented in the absence of extracellular Ca(2+) pointing to additional mechanisms. As shown in this study, osmotic shock (950 mOsm) triggers sphingomyelin breakdown and formation of ceramide. The stimulation of annexin binding following osmotic shock is mimicked by addition of ceramide or purified sphingomyelinase and significantly blunted by genetic (aSM-deficient mice) or pharmacologic (50 microM 3,4-dichloroisocoumarin) knockout of sphingomyelinase. The effect of ceramide is blunted but not abolished in the absence of Ca(2+). Conversely, osmotic shock-induced annexin binding is potentiated in the presence of sublethal concentrations of ceramide. In conclusion, ceramide and Ca(2+) entry through cation channels concert to trigger erythrocyte death during osmotic shock.
Lang
K S
KS
Department of Physiology, University of Tübingen, Gmelinstr. 5, 72076 Tübingen, Germany.
Myssina
S
S
Brand
V
V
Sandu
C
C
Lang
P A
PA
Berchtold
S
S
Huber
S M
SM
Lang
F
F
Wieder
T
T
D000818:Animals; D017302:Annexins / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D048429:Cell Size / Q000187:drug effects; D002518:Ceramides / Q000096:biosynthesis / Q000378:metabolism* / Q000494:pharmacology; D003374:Coumarins / Q000494:pharmacology; D004912:Erythrocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D037341:Fumonisins / Q000494:pharmacology; D006801:Humans; D015759:Ionomycin / Q000494:pharmacology; D049934:Isocoumarins; D051379:Mice; D018345:Mice, Knockout; D009997:Osmotic Pressure / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D013108:Sphingomyelin Phosphodiesterase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D013109:Sphingomyelins / Q000378:metabolism
D017302:Annexins; D002518:Ceramides; D003374:Coumarins; D037341:Fumonisins; D049934:Isocoumarins; D013109:Sphingomyelins; C056933:fumonisin B1; C046235:3,4-dichloroisocoumarin; D015759:Ionomycin; D013108:Sphingomyelin Phosphodiesterase; D020169:Caspases; D002118:Calcium