Inhibitory Effects of Metals on ATP-Induced Current Through P2X₇ Receptor in NG108-15 Cells

Abstract

We investigated the effects of heavy metal ions on the ATP-induced nonselective cation current through P2X₇ receptor (I_{NS · P2X7}) in NG108-15 cells using the whole-cell patch-clamp technique. Cu²⁺ inhibited the I_{NS · P2X7} most potently among the metal ions investigated. Other metals such as Ni²⁺, Cd²⁺, Zn²⁺ and Co²⁺ also inhibited the I_{NS · P2X7} in concentration-dependent manners. The order of potency was Cu²⁺ >> Ni²⁺ > Cd²⁺ > Zn²⁺ > Co²⁺ with IC₅₀ values of 16 nM, 0.79 μM, 1.2 μM, 3.0 μM and 4.6 μM, respectively. Fe³⁺ (10 and 100 μM) and Mn²⁺ (10 μM) did not affect the I_{NS · P2X7}. A high concentration of Mn²⁺ (100 μM) slightly inhibited the I_{NS · P2X7}. When the concentration-response curve of ATP was obtained in the presence of 3 and 10 nM Cu²⁺, the maximal response but not the EC₅₀ value appeared to be reduced, suggesting that the inhibition is not competitive. These results suggest that under physiological and toxicological conditions, metal ions, such as Cu²⁺, Ni²⁺, Cd²⁺, Zn²⁺ and Co²⁺, may modulate P2X₇ receptor channels as inhibitors.