Intracellular K(+) inhibits apoptosis by suppressing the Apaf-1 apoptosome formation and subsequent downstream pathways but not cytochrome c release.
Cellular ionic homeostasis, fundamentally K(+) homeostasis, has been implicated as a critical regulator of apoptosis. The intracellular K(+) efflux on apoptotic insult and suppression of apoptosis by high concentration of extracellular K(+) or after inhibition of this efflux by K(+) channel blockers have established the crucial role of K(+) in turning on the apoptotic machinery. Several contrasting observations have reported the antiapoptotic effect of intracellular K(+) concentration to be the result of inhibition of cytochrome c release from mitochondria, but the exact inhibitory mechanism remains obscure. However, here we show the blockage of K(+) efflux during apoptosis did not affect cytochrome c release from the mitochondria, still completely inhibited the formation of the apoptosome comprising Apaf-1, cytochrome c, caspase-9 and other accessories. As a consequence of this event, procaspase-9, -3, -8 and other death-related proteins were not processed. Furthermore, physiological concentrations of K(+) also inhibited the processing of procaspase-3 by purified caspase-8 or -9, the nucleosomal DNA fragmentation by purified DFF40/CAD and the nuclear fragmentation to varying extents. Altogether, these findings suggest that the efflux of K(+) is prerequisite not only for the formation of the apoptosome but also for the downstream apoptotic signal-transduction pathways.
Karki
P
P
Department of Bio-Materials Engineering and Cellular and Molecular Medicine, School of Medicine, Research Center for Proteineous Materials (RCPM), Chosun University, Gwangju, Korea.
Seong
C
C
Kim
J-E
JE
Hur
K
K
Shin
S Y
SY
Lee
J S
JS
Cho
B
B
Park
I-S
IS
D017209:Apoptosis; D053478:Apoptosomes / Q000378:metabolism*; D053477:Apoptotic Protease-Activating Factor 1 / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D002457:Cell Extracts; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002474:Cell-Free System; D045304:Cytochromes c / Q000378:metabolism*; D053938:DNA Fragmentation / Q000187:drug effects; D003838:Deoxyadenine Nucleotides / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D007424:Intracellular Fluid / Q000378:metabolism*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D008954:Models, Biological; D011188:Potassium / Q000378:metabolism* / Q000494:pharmacology; D019311:Staurosporine / Q000494:pharmacology; D013379:Substrate Specificity / Q000187:drug effects
D053478:Apoptosomes; D053477:Apoptotic Protease-Activating Factor 1; D002457:Cell Extracts; D003838:Deoxyadenine Nucleotides; D045304:Cytochromes c; D053148:Caspase 3; D053453:Caspase 9; D019311:Staurosporine; D011188:Potassium