A Role for Mitogen-activated Protein KinaseErk1/2Activation and Non-selective Pore Formation in P2X7 Receptor-mediated Thymocyte Death

Rodolphe Auger, Iris Motta, Karim Benihoud, David M. Ojcius, Jean M. Kanellopoulos
2005 Journal of Biological Chemistry  
2005) . A role for mitogen-activated protein kinase (Erk1/2) activation and non-selective pore formation in P2X7 receptor-mediated thymocyte death. Extracellular ATP (ATPe) binds to P2X7 receptors (P2X7R) expressed on the surface of cells of hematopoietic lineage, including murine thymocytes. Activation of P2X7R by ATPe results in the opening of cation-specific channels, and prolonged ATPe exposure leads to the formation of non-selective pores enabling transmembrane passage of solutes up to 900
more » ... Da. In the presence of ATPe, P2X7R-mediated thymocyte death is due primarily to necrosis/lysis and not apoptosis, as measured by the release of lactate dehydrogenase indicative of a loss of plasma membrane integrity. The present study is focused on the identification of P2X7R signaling mediators in ATP-induced thymocyte necrosis/lysis. Thus, extracellular signal-regulated protein kinase 1/2 (Erk1/2) phosphorylation was found to be required for cell lysis, and both events were independent of ATP-induced calcium influx. P2X7R-dependent thymocyte death involved the chronological activation of Src family tyrosine kinase(s), phosphatidylinositol 3-kinase, the mitogen-activated protein (MAP) kinase Erk1/2 module, and the proteasome. Although independent of this signaling cascade, non-selective pore formation may modulate ATP-mediated thymocyte death. These results therefore suggest a role for both activation of MAP kinase Erk1/2 and non-selective pore opening in P2X7R-induced thymocyte death.
doi:10.1074/jbc.m501290200 pmid:15937334 fatcat:cecjluaukrgjhd4s6ktfey2sie