Mechanism of TRPM2 channel gating revealed by cryo-EM

Transient receptor potential melastatin 2 (TRPM2) is a non-selective cation channel that allows Ca²⁺ influx across the plasma membrane and efflux from lysosomes upon opening. TRPM2 is best known as a biosensor of reactive oxygen species (ROS), which mediates some of the body's responses to oxidative stress. As such, TRPM2 is involved in a plethora of biological processes including immune response, insulin secretion, body temperature control and neuronal cell death, and represents an emerging therapeutic target for many human diseases, from diabetes to inflammatory and neurodegenerative diseases. A direct ligand of TRPM2 is ADP-ribose (ADPR), which accumulates in cells at high levels of ROS, and activates TRPM2 synergistically with intracellular calcium (Ca²⁺ ). Here, we describe recent cryo-electron microscopy (cryo-EM) structures of TRPM2 and summarize the insights they provided into the gating mechanism of the channel.