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Vol. 14, Issue 7, 2655-2664, July 2003
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*Department of Experimental and Diagnostic
Medicine, Section of General Pathology, and Interdisciplinary Center for the
Study of Inflammation (ICSI), University of Ferrara, I-44100 Ferrara, Italy;
and Abramson Family Cancer Research Institute,
BRB II/III, University of Pennsylvania, Philadelphia, Pennsylvania 19104
Submitted April 22, 2002;
Revised January 27, 2003;
Accepted March 17, 2003
Monitoring Editor: Guido Guidotti
The P2X7 ATP receptor mediates the cytotoxic effect of extracellular ATP. P2X7-dependent cell death is heralded by dramatic plasma membrane bleb formation. Membrane blebbing is a complex phenomenon involving as yet poorly characterized intracellular pathways. We have investigated the effect of extracellular ATP on HEK293 cells transfected with the cytotoxic/pore-forming P2X7 receptor. Addition of ATP to P2X7-transfected, but not to wt P2X7-less, HEK293 cells caused massive membrane blebbing within 1–2 min. UTP, a nucleotide incapable of activating P2X7, had no early effects on cell shape and bleb formation. Bleb formation triggered by ATP was reversible and required extracellular Ca2+ and an intact cytoskeleton. Furthermore, it was completely prevented by preincubation with the P2X blocker oxidized ATP. It was recently observed that the ROCK protein is a key determinant of bleb formation. Preincubation of HEK293-P2X7 cells with the ROCK blocker Y-27632 completely prevented P2X7-dependent blebbing. Although ATP triggered cleavage of the ROCK I isoform in P2X7-transfected HEK293 cells, the wide range caspase inhibitor z-VAD-fluoromethylketone had no effect. These observations suggest that P2X7-dependent plasma membrane blebbing depends on the activation of the serine/threonine kinase ROCK I.
Abbreviations used: GFP, green fluorescent protein; MLC, myosin light chain; oATP, oxidized ATP; TNFRI, type I TNF receptor.
Online version of this article contains video material. Online version is
available at
www.molbiolcell.org.
Corresponding author. E-mail address:
fdv{at}unife.it.
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