Zinc (Zn2+) and copper (Cu2+) are key signalling molecules in the immune system and regulate the activity of many ion channels. Both Zn2+ and Cu2+ potently inhibit rat P2X(7) receptors via a binding site identified by mutagenesis. Here we show that extracellular Cu2+ also potently inhibits mouse P2X(7) receptors. By contrast, the receptor expression system and agonist strongly influence the action of extracellular Zn2+ at mouse P2X(7) receptors. Consistent with previous reports, Zn2+ inhibits recombinant rat P2X(7) receptors. However, recombinant mouse P2X(7) receptors are potentiated by Zn2+ when activated by ATP(4-) but inhibited when stimulated with the ATP analogue BzATP(4-). Endogenous murine macrophage P2X(7) receptors are not modulated by Zn2+ when stimulated by ATP(4-) however Z(2+), inhibits BzATp(4-) mediated responses. in summary, these findings provide a fundamental insight into the differential actions of Zn" and Cu" between different P2X(7) receptor species.