Evidence for two conductive pathways in P2X7 receptor: differences in modulation and selectivity


Address correspondence and reprint requests to Dr Mario Nobile, Institute of Biophysics, CNR, Via De Marini, 6 – 16149 Genoa, Italy. E-mail: nobile@ge.ibf.cnr.it


J. Neurochem. (2010) 113, 796–806.


The P2X7 receptor (P2X7R) is an ATP-gated cation channel whose biophysical properties remain to be unravelled unequivocally. Its activity is modulated by divalent cations and organic messengers such as arachidonic acid (AA). In this study, we analysed the differential modulation of magnesium (Mg2+) and AA on P2X7R by measuring whole-cell currents and intracellular Ca2+ ([Ca2+]i) and Na+ ([Na+]i) dynamics in HEK293 cells stably expressing full-length P2X7R and in cells endowed with the P2X7R variant lacking the entire C-terminus tail (trP2X7R), which is thought to control the pore activation. AA induced a robust potentiation of the P2X7R- and trP2X7R-mediated [Ca2+]i rise but did not affect the ionic currents in both conditions. Extracellular Mg2+ reduced the P2X7R- and trP2X7R-mediated [Ca2+]i rise in a dose-dependent manner through a competitive mechanism. The modulation of the magnitude of the P2X7R-mediated ionic current and [Na+]i rise were strongly dependent on Mg2+ concentration but occurred in a non-competitive manner. In contrast, in cells expressing the trP2X7R, the small ionic currents and [Na+]i signals were totally insensitive to Mg2+. Collectively, these results support the tenet of a functional structure of P2X7R possessing at least two distinct conductive pathways one for Ca2+ and another for monovalent ions, with the latter which depends on the presence of the receptor C-terminus.