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J. Biol. Chem., Vol. 280, Issue 40, 33968-33976, October 7, 2005

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Pseudoapoptosis Induced by Brief Activation of ATP-gated P2X₇ Receptors^*

From the Department of Biomedical Science, Institute of Molecular Physiology, University of Sheffield, Western Bank, Sheffield S10 2TN, United Kingdom

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.

Received for publication, March 11, 2005 , and in revised form, June 29, 2005.

^* This work was supported by the Wellcome Trust. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental movies.

¹ To whom correspondence should be addressed: Inst. of Molecular Physiology, Dept. Biomedical Science Addison Bldg., Western Bank, University of Sheffield, S10 2TN, UK. Tel.: 44-114-222-2366; Fax: 44-114-222-2360; E-mail: a.surprenant{at}sheffield.ac.uk.

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