We studied by patch clamping the influence of external alkali and organic monovalent cations of increasing size on the single channel properties of the ATP-activated recombinant human P2X7 receptor. From the relationship between single channel conductance and the dimensions of the inward current carrier, the narrowest portion of the was estimated to have a mean diameter of 8.5 A. Substitution of extracellular Na+ by any other alkali or organic cations drastically increased the open probability of the channels by prolonging the mean open time. This effect seems to be mediated allosterically through an extracellular voltage- dependent Na+ binding site. The modulation of the ATP-induced hP2X7 receptor gating by extracellular Na+ could be well described by altering the rate constant from the open to the neighboring closed state in a C-C-C-O kinetic receptor model. We suggest that P2X7 receptor-induced depolarization and associated K+ -efflux may reduce Na+ occupancy of the regulatory Na+ binding site and thus increase both the efficacy and potency of ATP in a feed forward manner in P2X7 receptor expressing cells.

This work was supported by the Deutsche Forschungs- gemeinschaft (Ma 1581/12-1)Address of G. Schmalzing: RWTH Aachen, Department for Molecular Pharmacology, Wendlingweg 2, D-52074 Aachen