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J. Biol. Chem., Vol. 279, Issue 30, 31287-31295, July 23, 2004

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An Arg³⁰⁷ to Gln Polymorphism within the ATP-binding Site Causes Loss of Function of the Human P2X₇ Receptor^*

Ben J. Gu, Ronald Sluyter, Kristen K. Skarratt, Anne N. Shemon, Lan-Phuong Dao-Ung, Stephen J. Fuller, Julian A. Barden, Alison L. Clarke¶, Steven Petrou¶, and James S. Wiley||

From the Department of Medicine, University of Sydney at Nepean Hospital, Penrith, New South Wales 2750, the Department of Anatomy and Histology, University of Sydney, Sydney, New South Wales 2006, and the ^¶Howard Florey Institute, University of Melbourne, Victoria 3010, Australia

The P2X₇ receptor is a ligand-gated channel that is highly expressed on mononuclear cells of the immune system and that mediates ATP-induced apoptosis. Wide variations in the function of the P2X receptor have been observed, explained in part by ⁷loss-of-function polymorphisms that change Glu⁴⁹⁶ to Ala (E496A) and Ile⁵⁶⁸ to Asn (I568N). In this study, a third polymorphism, which substitutes an uncharged glutamine for the highly positively charged Arg³⁰⁷ (R307Q), has been found in heterozygous dosage in 12 of 420 subjects studied. P2X₇ function was measured by ATP-induced fluxes of Rb⁺, Ba²⁺, and ethidium⁺ into peripheral blood monocytes or various lymphocyte subsets and was either absent or markedly decreased. Transfection experiments showed that P2X₇ carrying the R307Q mutation lacked either channel or pore function despite robust protein synthesis and surface expression of the receptor. The monoclonal antibody (clone L4) that binds to the extracellular domain of wild type P2X₇ and blocks P2X₇ function failed to bind to the R307Q mutant receptor. Differentiation of monocytes to macrophages up-regulated P2X₇ function in cells heterozygous for the R307Q to a value 10–40% of that for wild type macrophages. However, macrophages from a subject who was double heterozygous for R307Q/I568N remained totally non-functional for P2X₇, and lymphocytes from the same subject also lacked ATP-stimulated phospholipase D activity. These data identify a third loss-of-function polymorphism affecting the human P2X₇ receptor, and since the affected Arg³⁰⁷ is homologous to those amino acids essential for ATP binding to P2X₁ and P2X₂, it is likely that this polymorphism abolishes the binding of ATP to the extracellular domain of P2X₇.

Received for publication, December 19, 2003 , and in revised form, April 8, 2004.

^* This work was supported by the National Health and Medical Research Council, the Cure Cancer Australia Foundation, the Leukemia Foundation of Australia, and a Sesqui Fellowship from the University of Sydney (to B. J. G.). 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: Nepean Hospital, Level 5, South Block, Penrith, New South Wales 2750, Australia. Tel.: 61-2-4734-3277; Fax: 61-2-4734-3432; E-mail: wileyj{at}medicine.usyd.edu.au.

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