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J. Biol. Chem., Vol. 279, Issue 43, 44749-44755, October 22, 2004

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Extracellular ATP Increases Cation Fluxes in Human Erythrocytes by Activation of the P2X₇ Receptor^*

Ronald Sluyter, Anne N. Shemon¶, Julian A. Barden||, and James S. Wiley**

From the Department of Medicine, University of Sydney at Nepean Hospital and ^**the Department of Pathology, Nepean Hospital, Penrith, New South Wales 2750, Australia and the ^||Biosceptre Research Laboratory, Institute for Biomedical Research and Department of Anatomy and Histology, University of Sydney, Sydney, New South Wales 2006, Australia

Canine erythrocytes are known to undergo a reversible increase in cation permeability when incubated with extracellular ATP. We have examined the expression and function of P2X receptors on human erythrocytes using confocal microscopy and a panel of anti-P2X_1–7 antibodies and have measured monovalent cation fluxes in the presence of various nucleotide agonists. Human erythrocytes expressed P2X₇ receptors on all cells examined from eight of eight subjects, as well as P2X₂ at a far lower staining intensity in six of eight subjects. ATP stimulated the efflux of ⁸⁶Rb⁺ (K⁺) from human erythrocytes in a dose-dependent fashion with an EC₅₀ of 95 µM. Other nucleotides also induced an efflux of ⁸⁶Rb⁺ from erythrocytes with an order of agonist potency of 2'- and 3'-O(4-benzoylbenzoyl) ATP (BzATP) > ATP > 2-methylthio-ATP (2MeSATP) > adenosine 5'-O-(3-thiotriphosphate) (ATPS), whereas ADP or UTP had no effect. ATP-induced efflux of ⁸⁶Rb⁺ from erythrocytes was inhibited by extracellular Na⁺ and oxidized ATP, as well as by KN-62, an antagonist specific for the human P2X₇ receptor. When erythrocytes were incubated in isotonic KCl medium, the addition of ATP stimulated an ⁸⁶Rb⁺ influx approximately equal in magnitude to ATP-stimulated ⁸⁶Rb⁺ efflux from the same cells. BzATP also stimulated the influx of ²²Na⁺ into erythrocytes incubated in isotonic NaCl medium. Both ATP-induced efflux and influx of ⁸⁶Rb⁺ and ²²Na⁺ were impaired in erythrocytes from subjects who had inherited loss-of-function polymorphisms in the P2X₇ receptor. These results suggest that the reversible permeabilization of erythrocytes by extracellular ATP is mediated by the P2X₇ receptor.

Received for publication, May 20, 2004 , and in revised form, August 5, 2004.

^* This work was supported by the National Health and Medical Research Council of Australia and the Leukemia Foundation of New South Wales. 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.

Both authors contributed equally to this work.

^¶ Recipient of a Faculty of Medicine Postgraduate Award from the University of Sydney.

To whom correspondence should be addressed: Level 5 South Block, Nepean Hospital, Penrith, NSW 2750, Australia. Tel.: 61-2-4734-3277; Fax: 61-2-4734-3432; E-mail: wileyj{at}medicine.usyd.edu.au.

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