Regulation of the P2X7 receptor permeability to large molecules by extracellular Cl- and Na+

Qin Li, Xiang Luo, Shmuel Muallem

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)26922-26927
Number of pages6
JournalJournal of Biological Chemistry
Volume280
Issue number29
DOIs
StatePublished - Jul 22 2005

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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