Transient receptor potential melastatin 2 (TRPM2) is a Ca2+-permeable cationic channel in the TRP channel family. The channel activity can be regulated by reactive oxygen species (ROS) and cellular acidification, which has been implicated to the pathogenesis of diabetes and some neuronal disorders. However, little is known about the effect of redox-active metal ions, such as copper, on TRPM2 channels. Here we investigated the effect of divalent copper on TRPM2. TRPM2 channel was over-expressed in HEK-293 cells and the whole-cell current was recorded by patch clamp. We found the whole-cell current evoked by intracellular ADP-ribose was potently inhibited by Cu2+ with a half maximal inhibitory concentration (IC50) of 2.59 mu M. The inhibitory effect was irreversible. The single channel activity was abolished in the outside-out patches, and intracellular application of Cu2+ did not prevent the channel activation, suggesting that the action site of Cu2+ is located in the extracellular domains of the channel. TRPM2 current was also blocked by Hg2+, Pb2+, Fe2+ and Se2+. We concluded that Cu2+ is a potent TRPM2 channel blocker. The sensitivity of TRPM2 channel to heavy metal ions could be a new mechanism for the pathogenesis of some metal ion-related diseases. (C) 2012 Elsevier Inc. All rights reserved.