Species and agonist dependent zinc modulation of endogenous and recombinant ATP-gated P2X 7 receptors

Abstract

Zinc (Zn 2+) and copper (Cu 2+) are key signalling molecules in the immune system and regulate the activity of many ion channels. Both Zn 2+ and Cu 2+ potently inhibit rat P2X 7 receptors via a binding site identified by mutagenesis. Here we show that extracellular Cu 2+ also potently inhibits mouse P2X 7 receptors. By contrast, the receptor expression system and agonist strongly influence the action of extracellular Zn 2+ at mouse P2X 7 receptors. Consistent with previous reports, Zn 2+ inhibits recombinant rat P2X 7 receptors. However, recombinant mouse P2X 7 receptors are potentiated by Zn 2+ 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 Zn 2+ when stimulated by ATP 4− however Zn 2+ inhibits BzATP 4− mediated responses. In summary, these findings provide a fundamental insight into the differential actions of Zn 2+ and Cu 2+ between different P2X 7 receptor species.