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J. Biol. Chem., Vol. 280, Issue 30, 28142-28151, July 29, 2005

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A Role for Mitogen-activated Protein Kinase^Erk1/2 Activation and Non-selective Pore Formation in P2X7 Receptor-mediated Thymocyte Death^*

Rodolphe Auger, Iris Motta, Karim Benihoud, David M. Ojcius, and Jean M. Kanellopoulos¶

From the Institut de Biochimie et Biophysique Moléculaire et Cellulaire, Université Paris-Sud, 91405 Orsay cedex, France and the School of Natural Sciences, University of California, Merced, California 95344

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 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.

Received for publication, February 3, 2005 , and in revised form, June 3, 2005.

^* This work was supported by the Fondation pour la Recherche Médicale, Association de Recherche contre le Cancer, and CNRS. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: Laboratoire Activation Cellulaire et Transduction des Signaux, Institut de Biochimie et Biophysique Moléculaire et Cellulaire, UMR 8619, CNRS, Université Paris-Sud, Btiment 430, 91405 Orsay cedex, France. Tel.: 33-1-69-15-46-88; Fax: 33-1-69-85-37-15; E-mail: jean.kanellopoulos{at}ibbmc.u-psud.fr.

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