Human P2X7 receptors were expressed in Xenopus laevis oocytes and single channel currents were recorded using the patch clamp technique in the outside-out configuration. The open probabilities were strongly [ATP4-]-dependent with EC50 values of ~0.3 mM and ~0.1 mM ATP4-, respectively. Activation and deactivation followed exponential time courses with time constants in the range of 20 ms, and displayed a shallow [ATP4-] dependence of the activation process. The kinetics of the channel openings at negative membrane potentials fitted well to a linear C-C-C-O model with two ATP4-- binding steps at equal binding sites. Single channel kinetics and permeation properties remained unchanged during receptor activation by up to 1 mM ATP4- for more than 1 min, arguing against a molecular correlate of pore dilation at the single P2X7 channel level. From the relationship between single channel conductance and the dimensions of the inward current carrier, the narrowest portion of the pore was estimated to have a mean diameter of ~8.5 Å. Substitution of extracellular Na+ by any other alkali or organic cation drastically increased the open probability of the channels by prolonging the mean open time. This effect seems to be mediated allosterically through an extracellular Na+ binding site with a Kd of about 5 mM Na+ at a membrane potential of -120 mV. 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. P2X7 receptor-induced depolarization and associated K+-efflux may reduce Na+ occupancy of the regulatory Na+ binding site and thus increase the efficacy of ATP4- in a feed-forward manner in P2X7 receptor-expressing cells.