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

The P2X(7) receptor (P2X(7)R) 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 (Mg(2+)) and AA on P2X(7)R by measuring whole-cell currents and intracellular Ca(2+) ([Ca(2+)](i)) and Na(+) ([Na(+)](i)) dynamics in HEK293 cells stably expressing full-length P2X(7)R and in cells endowed with the P2X(7)R variant lacking the entire C-terminus tail (trP2X(7)R), which is thought to control the pore activation. AA induced a robust potentiation of the P2X(7)R- and trP2X(7)R-mediated [Ca(2+)](i) rise but did not affect the ionic currents in both conditions. Extracellular Mg(2+) reduced the P2X7R- and trP2X(7)R-mediated [Ca(2+)](i) rise in a dose-dependent manner through a competitive mechanism. The modulation of the magnitude of the P2X(7)R-mediated ionic current and [Na(+)](i) rise were strongly dependent on Mg(2+) concentration but occurred in a non-competitive manner. In contrast, in cells expressing the trP2X(7)R, the small ionic currents and [Na(+)](i) signals were totally insensitive to Mg(2+). Collectively, these results support the tenet of a functional structure of P2X(7)R possessing at least two distinct conductive pathways one for Ca(2+) and another for monovalent ions, with the latter which depends on the presence of the receptor C-terminus.