Architecture of the TRPM2 channel and its activation mechanism by ADP-ribose and calcium

Transient receptor potential melastatin 2 (TRPM2) is a calcium-permeable, non-selective cation channel that has an essential role in diverse physiological processes such as core body temperature regulation, immune response and Apoptosis^1-4. TRPM2 is polymodal and can be activated by a wide range of stimuli^1-7, including temperature, oxidative stress and NAD⁺-related metabolites such as ADP-ribose (ADPR). Its activation results in both CA²⁺ entry across the plasma membrane and CA²⁺ release from lysosomes⁸, and has been linked to diseases such as ischaemia-reperfusion injury, bipolar disorder and Alzheimer's disease^9-11. Here we report the cryo-electron microscopy structures of the zebrafish TRPM2 in the apo resting (closed) state and in the ADPR/CA²⁺-bound active (open) state, in which the characteristic NUDT9-H domains hang underneath the MHR1/2 domain. We identify an ADPR-binding site located in the bi-lobed structure of the MHR1/2 domain. Our results provide an insight into the mechanism of activation of the TRPM channel family and define a framework for the development of therapeutic agents to treat neurodegenerative diseases and temperature-related pathological conditions.