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Vol. 16, Issue 7, 3260-3272, July 2005

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Basal Activation of the P2X₇ ATP Receptor Elevates Mitochondrial Calcium and Potential, Increases Cellular ATP Levels, and Promotes Serum-independent Growth

Department of Experimental and Diagnostic Medicine, Section of General Pathology, and Interdisciplinary Center for the Study of Inflammation, University of Ferrara, 44100 Ferrara, Italy

Submitted November 23, 2004; Revised May 4, 2005; Accepted May 6, 2005
Monitoring Editor: Guido Guidotti

P2X₇ is a bifunctional receptor (P2X₇R) for extracellular ATP that, depending on the level of activation, forms a cation-selective channel or a large conductance nonselective pore. The P2X₇R has a strong proapoptotic activity but can also support growth. Here, we describe the mechanism involved in growth stimulation. Transfection of P2X₇R increases resting mitochondrial potential (^mt), basal mitochondrial Ca²⁺ ([Ca²⁺]_mt), intracellular ATP content, and confers ability to grow in the absence of serum. These changes require a full pore-forming function, because they are abolished in cells transfected with a mutated P2X₇R that retains channel activity but cannot form the nonselective pore, and depend on an autocrine/paracrine tonic stimulation by secreted ATP. On the other hand, sustained stimulation of P2X₇R causes a _mt drop, a large increase in [Ca²⁺]_mt, mitochondrial fragmentation, and cell death. These findings reveal a hitherto undescribed mechanism for growth stimulation by a plasma membrane pore.

Abbreviations used: BzATP, benzoyl ATP; [Ca²⁺]_i, cytosolic Ca²⁺ concentration; [Ca²⁺]_mt, mitochondrial Ca²⁺ concentration; _mt, mitochondrial potential; ER, endoplasmic reticulum; FCCP, carbonyl cyanide a-[3-(2-benzothiazolyl)6-[2-[2-[bis(carboxymethyl)amino]-5-methylphenoxy]-2-oxo-2H-1-benzopyran-7yl]-b-(carboxymethyl)-tetrapotassium salt; mtAEQ, mitochondrial aequorin; mt-GFP, mitochondrial green fluorescent protein; oATP, oxidized ATP; P2X₇R, P2X₇ receptor; P2X₇CR, truncated P2X₇ receptor; TMRM, tetramethylrhodamine methyl ester.

Address correspondence to: Francesco Di Virgilio (fdv{at}unife.it).

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