Plasma membrane potential in thymocyte apoptosis.
Apoptosis is accompanied by major changes in ion compartmentalization and transmembrane potentials. Thymocyte apoptosis is characterized by an early dissipation of the mitochondrial transmembrane potential, with transient mitochondrial swelling and a subsequent loss of plasma membrane potential (DeltaP sip) related to the loss of cytosolic K+, cellular shrinkage, and DNA fragmentation. Thus, a gross perturbation of DeltaPsip occurs at the postmitochondrial stage of apoptosis. Unexpectedly, we found that blockade of plasma membrane K+ channels by tetrapentylammonium (TPA), which leads to a DeltaP sip collapse, can prevent the thymocyte apoptosis induced by exposure to the glucocorticoid receptor agonist dexamethasone, the topoisomerase inhibitor etoposide, gamma-irradiation, or ceramide. The TPA-mediated protective effect extends to all features of apoptosis, including dissipation of the mitochondrial transmembrane potential, loss of cytosolic K+, phosphatidylserine exposure on the cell surface, chromatin condensation, as well as caspase and endonuclease activation. In strict contrast, TPA is an ineffective inhibitor when cell death is induced by the potassium ionophore valinomycin, the specific mitochondrial benzodiazepine ligand PK11195, or by primary caspase activation by Fas/CD95 cross-linking. These results underline the importance of K+ channels for the regulation of some but not all pathways leading to thymocyte apoptosis.
Dallaporta
B
B
Centre National de Recherche Scientifique, Unité Propre de Recherche 420, Villejuif, France.
Marchetti
P
P
de Pablo
M A
MA
Maisse
C
C
Duc
H T
HT
Métivier
D
D
Zamzami
N
N
Geuskens
M
M
Kroemer
G
G
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology* / Q000502:physiology; D002462:Cell Membrane / Q000187:drug effects / Q000502:physiology / Q000648:ultrastructure; D003907:Dexamethasone / Q000494:pharmacology; D005047:Etoposide / Q000494:pharmacology; D005260:Female; D007425:Intracellular Membranes / Q000187:drug effects / Q000502:physiology / Q000648:ultrastructure; D008564:Membrane Potentials / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology / Q000648:ultrastructure; D026902:Potassium Channel Blockers; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013950:Thymus Gland / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure
D026902:Potassium Channel Blockers; D005047:Etoposide; D003907:Dexamethasone; D013755:Tetradecanoylphorbol Acetate