Sequential shrinkage and swelling underlie P2X7-stimulated lymphocyte phosphatidylserine exposure and death.
Patterns of change in cell volume and plasma membrane phospholipid distribution during cell death are regarded as diagnostic means of distinguishing apoptosis from necrosis, the former being associated with cell shrinkage and early phosphatidylserine (PS) exposure, whereas necrosis is associated with cell swelling and consequent lysis. We demonstrate that cell volume regulation during lymphocyte death stimulated via the purinergic receptor P2X7 is distinct from both. Within seconds of stimulation, murine lymphocytes undergo rapid shrinkage concomitant with, but also required for, PS exposure. However, within 2 min shrinkage is reversed and swelling ensues ending in cell rupture. P2X7-induced shrinkage and PS translocation depend upon K+ efflux via KCa3.1, but use a pathway of Cl- efflux distinct from that previously implicated in apoptosis. Thus, P2X7 stimulation activates a novel pathway of cell death that does not conform to those conventionally associated with apoptosis and necrosis. The mixed apoptotic/necrotic phenotype of P2X7-stimulated cells is consistent with a potential role for this death pathway in lupus disease.
Taylor
Simon R J
SR
Medical Research Council, Clinical Sciences Centre, Faculty of Medicine, Imperial College, London, United Kingdom.
Gonzalez-Begne
Mireya
M
Dewhurst
Stephen
S
Chimini
Giovanna
G
Higgins
Christopher F
CF
Melvin
James E
JE
Elliott
James I
JI
D000818:Animals; D017209:Apoptosis; D001692:Biological Transport / Q000187:drug effects; D048429:Cell Size; D002712:Chlorides / Q000378:metabolism; D017630:Connexins; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000037:antagonists & inhibitors / Q000378:metabolism; D050356:Lipid Metabolism; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D008213:Lymphocyte Activation; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology*; D051379:Mice; D008815:Mice, Inbred Strains; D009419:Nerve Tissue Proteins; D010718:Phosphatidylserines / Q000378:metabolism* / Q000494:pharmacology; D058910:Purinergic P2 Receptor Agonists; D018048:Receptors, Purinergic P2 / Q000378:metabolism*; D058486:Receptors, Purinergic P2X7; D013601:T-Lymphocytes / Q000276:immunology; D013629:Tamoxifen / Q000494:pharmacology
D002712:Chlorides; D017630:Connexins; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; C496925:Kcnn4 protein, mouse; D009419:Nerve Tissue Proteins; C546469:P2rx7 protein, mouse; C503631:Panx1 protein, mouse; D010718:Phosphatidylserines; D058910:Purinergic P2 Receptor Agonists; D018048:Receptors, Purinergic P2; D058486:Receptors, Purinergic P2X7; D013629:Tamoxifen