Pseudoapoptosis induced by brief activation of ATP-gated P2X7 receptors.
P2X7 receptors are ATP-gated ion channels primarily expressed on antigen-presenting immune cells where they play a role in the acute inflammatory response. These ion channels couple not only to influx of cations, including calcium, but also to rapid alterations in cell morphology (membrane blebbing, phosphatidylserine exposure, microvesicle shedding). These features resemble the extranuclear events associated with end stages of apoptosis but cell death does not occur if receptor activation is brief. Here we delineate two signaling pathways underlying these apoptotic-like processes. Loss of membrane asymmetry occurs within seconds, which directly triggers cytoskeletal disruption and zeiotic membrane blebbing; this is readily reversible and requires both calcium influx through P2X7 channels and mitochondrial calcium increase but is not associated with cytochrome c release. A slower, calcium-independent, ROCK-1-dependent cascade that does not involve rapid loss of membrane asymmetry but is associated with cytochrome c release is secondarily activated. The ROCK-1 pathway appears largely responsible for cell death, which occurs after prolonged stimulation of P2X7 receptors. We suggest that the former mechanism underlies the reversible pseudoapoptotic events induced by brief activation of P2X7 receptors.
Mackenzie
Amanda B
AB
Department of Biomedical Science, Institute of Molecular Physiology, University of Sheffield, Western Bank, Sheffield S10 2TN, United Kingdom.
Young
Mark T
MT
Adinolfi
Elena
E
Surprenant
Annmarie
A
D000255:Adenosine Triphosphate / Q000502:physiology*; D017209:Apoptosis / Q000235:genetics* / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D002462:Cell Membrane / Q000502:physiology*; D045304:Cytochromes c / Q000378:metabolism; D003599:Cytoskeleton / Q000648:ultrastructure; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007668:Kidney / Q000166:cytology; D008928:Mitochondria / Q000648:ultrastructure; D017346:Protein Serine-Threonine Kinases; D018048:Receptors, Purinergic P2 / Q000502:physiology*; D058486:Receptors, Purinergic P2X7; D015398:Signal Transduction; D054460:rho-Associated Kinases
D047908:Intracellular Signaling Peptides and Proteins; C546468:P2RX7 protein, human; D018048:Receptors, Purinergic P2; D058486:Receptors, Purinergic P2X7; D000255:Adenosine Triphosphate; D045304:Cytochromes c; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D002118:Calcium