Divalent copper is a potent extracellular blocker for TRPM2 channel

Area of Science:

• Ion channel physiology
• Molecular pharmacology
• Redox signaling

Background:

• Transient receptor potential melastatin 2 (TRPM2) channels are calcium-permeable cation channels involved in cellular responses to reactive oxygen species (ROS) and acidification.
• TRPM2 dysfunction is implicated in diabetes and neurological disorders.
• The impact of redox-active metal ions, like copper, on TRPM2 channel activity remains largely unexplored.

Purpose of the Study:

• To investigate the effect of divalent copper (Cu2+) on the function of TRPM2 channels.
• To determine the inhibitory concentration and mechanism of copper's action on TRPM2.

Main Methods:

• Overexpression of TRPM2 channels in HEK-293 cells.
• Whole-cell patch-clamp electrophysiology to record TRPM2 currents.
• Application of various divalent metal ions (Cu2+, Hg2+, Pb2+, Fe2+, Se2+) to assess channel inhibition.

Main Results:

• Divalent copper (Cu2+) potently inhibited TRPM2 currents with an IC50 of 2.59 μM.
• The inhibitory effect of Cu2+ was irreversible and abolished single-channel activity in outside-out patches.
• Copper's action site appears to be on the extracellular domains of the TRPM2 channel.
• Other heavy metal ions like Hg2+, Pb2+, Fe2+, and Se2+ also blocked TRPM2 currents.

Conclusions:

• Copper (Cu2+) acts as a potent blocker of TRPM2 channels.
• The TRPM2 channel's sensitivity to heavy metal ions presents a potential novel mechanism in metal ion-related diseases.
• Further research into TRPM2-metal ion interactions could elucidate disease pathogenesis.