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J. Biol. Chem., Vol. 280, Issue 29, 26922-26927, July 22, 2005

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Regulation of the P2X7 Receptor Permeability to Large Molecules by Extracellular Cl^– and Na^+*

Qin Li, Xiang Luo, and Shmuel Muallem

From the Department of Physiology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9040

Upon continuous stimulation, the pore of the monovalent cation-selective P2X7 receptor (P2X7R) expands to accommodate large molecules such as N-methyl-D-glucamine (NMDG⁺). How the change in P2X7R permeability is regulated is not known. Here we report that extracellular Cl^– (Cl^–_o) regulates the outward current, whereas extracellular Na⁺ (Na⁺_o) regulates the inward current of large molecules by P2X7Rs. The P2X7R-mediated current was measured in parotid acinar and duct cells of wild type and P2X7R^–/– mice and in HEK293 cells expressing the human or mouse P2X7R isoforms. In symmetrical NaCl, triethylammonium chloride, and NMDG⁺ chloride solutions, the P2X7R current followed a linear current/voltage relationship. In symmetrical NaCl, removal of Cl^–_o reduced the inward Na⁺ current by 35% and the outward Na⁺ current by only 10%. By contrast, in the absence of Na⁺_i and the presence of Na⁺_o or NMDG⁺_o, the removal of Cl^–_o reduced the inward Na⁺ or NMDG⁺ currents by 35% but the outward NMDG⁺ current by >95%. The effect of Cl^–_o was half-maximal at 60 mM. Reducing Cl^–_i from 150 to 10 mM did not reproduce the effects of Cl^–_o. All currents were eliminated in P2X7R^–/– cells and reproduced by expressing the P2X7Rs in HEK cells. These findings suggest that Cl^–_o primarily regulates the outward P2X7R current of large molecules. When cells dialyzed with NMDG⁺ were stimulated in the presence of Na⁺_o, subsequent removal of Na⁺_o resulted in a strongly outward rectifying NMDG⁺ current, indicating maintained high selectivity for Na⁺ over NMDG⁺. During continuous incubation in Na⁺-free medium, the permeability of the P2X7Rs to NMDG⁺ gradually increased. On the other hand, when the cells were incubated in symmetrical NMDG⁺ and only then stimulated with ATP, the NMDG⁺ current by P2X7Rs followed a linear current/voltage relationship and did not change with time. These findings suggest that the P2X7R has a "Na⁺_o memory" and that Na⁺_o regulates the inward permeability of P2X7Rs to large molecules. The novel regulation of P2X7R outward and inward permeability to large molecules by Cl^–_o and Na⁺_o, respectively, may have an important protective function, particularly in secretory epithelial cells.

Received for publication, May 5, 2005 , and in revised form, May 26, 2005.

^* This work was supported by National Institutes of Health Grants DE12309 and DK38938 and Cystic Fibrosis Foundation Grant MUALLE01G0. 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: The University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd., Dallas, TX 75390-9040. Tel.: 214-648-2593; Fax: 214-645-6054; E-mail: shmuel.muallem{at}utsouthwestern.edu.

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