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Nature. 2018 Oct;562(7725):145-149. doi: 10.1038/s41586-018-0558-4. Epub 2018 Sep 24.

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

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Van Andel Research Institute, Grand Rapids, MI, USA.
Vollum Institute, Oregon Health & Science University, Portland, OR, USA.
Janelia Research Campus, Ashburn, VA, USA.
Van Andel Research Institute, Grand Rapids, MI, USA.
Van Andel Research Institute, Grand Rapids, MI, USA.


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 apoptosis1-4. TRPM2 is polymodal and can be activated by a wide range of stimuli1-7, 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 disease9-11. 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.

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