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. 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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Architecture of the TRPM2 Channel and Its Activation Mechanism by ADP-ribose and Calcium

Yihe Huang et al. Nature. .

Abstract

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.

Comment in

  • TRPM2 activation: Paradigm shifted?
    Fliegert R, Hölzer HT, Guse AH. Fliegert R, et al. Cell Calcium. 2018 Dec;76:132-134. doi: 10.1016/j.ceca.2018.11.001. Epub 2018 Nov 3. Cell Calcium. 2018. PMID: 30420160

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