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

Author

Listed:
  • Yihe Huang

    (Van Andel Research Institute)

  • Paige A. Winkler

    (Van Andel Research Institute)

  • Weinan Sun

    (Oregon Health & Science University
    Janelia Research Campus)

  • Wei Lü

    (Van Andel Research Institute)

  • Juan Du

    (Van Andel Research Institute)

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.

Suggested Citation

  • Yihe Huang & Paige A. Winkler & Weinan Sun & Wei Lü & Juan Du, 2018. "Architecture of the TRPM2 channel and its activation mechanism by ADP-ribose and calcium," Nature, Nature, vol. 562(7725), pages 145-149, October.
    • Handle: RePEc:nat:nature:v:562:y:2018:i:7725:d:10.1038_s41586-018-0558-4
    DOI: 10.1038/s41586-018-0558-4
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    Citations

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    Cited by:

    1. Yi-Yu Lin & Yan Lu & Chun-Yun Li & Xue-Fei Ma & Miao-Qing Shao & Yu-Hao Gao & Yu-Qing Zhang & Hai-Ning Jiang & Yan Liu & Yang Yang & Li-Dong Huang & Peng Cao & Heng-Shan Wang & Jin Wang & Ye Yu, 2024. "Finely ordered intracellular domain harbors an allosteric site to modulate physiopathological function of P2X3 receptors," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    2. Kirill D. Nadezhdin & Leonor Correia & Chamali Narangoda & Dhilon S. Patel & Arthur Neuberger & Thomas Gudermann & Maria G. Kurnikova & Vladimir Chubanov & Alexander I. Sobolevsky, 2023. "Structural mechanisms of TRPM7 activation and inhibition," Nature Communications, Nature, vol. 14(1), pages 1-15, December.

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