Structural and functional studies of the TRPM2 channel

TRPM2通道的结构和功能研究

基本信息

  • 批准号:
    10604261
  • 负责人:
  • 金额:
    $ 41.56万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2019
  • 资助国家:
    美国
  • 起止时间:
    2019-04-01 至 2025-03-31
  • 项目状态:
    未结题

项目摘要

Body temperature is strictly maintained in a narrow range to protect the delicate nerves in the brain and other body tissues, because improper body temperature gives rise to fever, brain injury, and stroke. TRPM2 is the major warmth-sensing receptor in the brain regulating core body temperature and preventing overheating as fever occurs. TRPM2 is a Ca2+-permeable, nonselective ion channel that is highly expressed in brain but is also found in the heart, vascular and smooth muscle, and immune cells. It is uniquely activated by Ca2+ and ADP ribose (ADPR), a product of the metabolism of NAD+ and a secondary messenger released upon oxidative stress. The activation of TRPM2 results in both Ca2+ entry across the plasma membrane and Ca2+ release from lysosomes. Therefore, TRPM2 plays fundamental role in Ca2+-dependent array of physiological processes and cellular functions from insulin secretion to immune response to cell death. It has been implicated in Alzheimer disease, stroke, and other neurodegenerative diseases. TRPM2 belongs to the TRPM (melastatin-like transient receptor potential) subfamily of the TRP superfamily. Despite sharing the characteristic TRPM N-terminal homology regions (MHRs) and C-terminal coiled-coil domains, TRPM2 is uniquely assembled with a C-terminal NHDT9-H domain, a homolog to the human mitochondrial ADP-ribose pyrophosphatase NUDT9. Functional studies, including binding assays, electrophysiology, and molecular simulations, provided a consensus view that ADPR binds to the NUDT9-H domain, but proof of the ADPR binding site is lacking, and the molecular basis for the action of the agonist ADPR on TRPM2 in the presence of calcium remains unknown. The gating of TRPM2 is further modulated by many molecules and ions that range from protons to nucleotides (cyclic ADPR, AMP, 8-Br-cADPR) to curcumin (which is isolated from rhizomes of Curcuma longa), acting by way of multiple mechanisms. At present, we don't know where these molecules and ions bind to TRPM2 or how they activate the channel or modulate its function. We have obtained two cryo-EM structures of zebrafish TRPM2 in the apo/closed and ADPR/Ca2+-bound open state, with the latter representing the first active state of TRPM family members. We identified a novel ADPR binding site that is located outside the NUDT9-H domain and was completely unknown before. Building on this preliminary data, we propose to continue the structural studies of TRPM2 combined with complementary electrophysiology experiments, binding assays, and X-ray crystallography, which will define the molecular basis for a comprehensive gating mechanism and pharmacology. These advances will provide a solid foundation for developing new drugs against neurodegenerative diseases and for a deeper understanding the function of the entire TRPM family.
严格地将体温保持在一个狭窄的范围内,以保护大脑和其他部位脆弱的神经 身体组织,因为不适当的体温会引起发烧、脑损伤和中风。TRPM2是 大脑中主要的温觉感受器,调节核心体温,防止过热 就会发烧。TRPM2是一种钙离子通透性的非选择性离子通道,在大脑中高度表达,但 在心脏、血管和平滑肌以及免疫细胞中也有发现。它唯一地被钙离子激活,并且 腺苷二磷酸核糖(ADPR),是NAD+代谢的产物,是一种在 氧化应激。TRPM2的激活导致钙离子跨质膜进入和钙离子内流 从溶酶体中释放。因此,TRPM2在钙离子依赖的生理信号通路中起着基础性作用。 从胰岛素分泌到对细胞死亡的免疫反应的过程和细胞功能。一直以来 与阿尔茨海默病、中风和其他神经退行性疾病有关。 TRPM2属于色氨酸蛋白超家族中的TRPM(Melastatin样瞬时受体电位)亚家族。 尽管共享特征的TRPM N-末端同源区域(MHR)和C-末端螺旋线圈 结构域,TRPM2唯一地与C-末端NHDT9-H结构域组装,该结构域与人类的同源物 线粒体ADP-核糖焦磷酸酶NUDT9。功能研究,包括结合分析, 电生理学和分子模拟提供了ADPR与NUDT9-H结合的一致观点 结构域,但缺乏ADPR结合位点的证据,以及激动剂作用的分子基础 钙离子存在时TRPM2上的ADPR尚不清楚。对TRPM2的选通进行进一步调制 由许多分子和离子组成,从质子到核苷酸(环ADPR、AMP、8-溴-cADPR)到 姜黄素(从姜黄根状茎中分离出来),通过多种机制发挥作用。在… 目前,我们不知道这些分子和离子与TRPM2结合的位置,也不知道它们如何激活通道或 调节其功能。我们获得了斑马鱼TRPM2在apo/闭合和ADPR/Ca~(2+)结合的开放状态下的两种冷冻-EM结构,后者代表了TRPM家族成员的第一活性状态。我们发现了一个新的ADPR结合位点,该结合位点位于NUDT9-H结构域外,以前完全未知。在这些初步数据的基础上,我们建议继续进行TRPM2的结构研究,结合互补的电生理学实验、结合分析和X射线结晶学,这将为全面的门控机制和药理学确定分子基础。这些进展将为我们提供坚实的 为开发治疗神经退行性疾病的新药和加深了解奠定基础 整个TRPM系列的功能。

项目成果

期刊论文数量(6)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
The structures and gating mechanism of human calcium homeostasis modulator 2.
  • DOI:
    10.1038/s41586-019-1781-3
  • 发表时间:
    2019-12
  • 期刊:
  • 影响因子:
    64.8
  • 作者:
    Choi W;Clemente N;Sun W;Du J;Lü W
  • 通讯作者:
    Lü W
Structures of human pannexin 1 reveal ion pathways and mechanism of gating.
  • DOI:
    10.1038/s41586-020-2357-y
  • 发表时间:
    2020-08
  • 期刊:
  • 影响因子:
    64.8
  • 作者:
    Ruan Z;Orozco IJ;Du J;Lü W
  • 通讯作者:
    Lü W
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Juan Du其他文献

Akt regulates the fertility of Coridius chinensis by insulin signaling pathway
阿克泰通过胰岛素信号通路调控中华稻蝗的生殖力
  • DOI:
    10.1038/s41598-024-78416-0
  • 发表时间:
    2024-11-20
  • 期刊:
  • 影响因子:
    3.900
  • 作者:
    Jinyu Feng;Juan Du;Shangwei Li;Xingxing Chen
  • 通讯作者:
    Xingxing Chen

Juan Du的其他文献

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{{ truncateString('Juan Du', 18)}}的其他基金

Structural Basis of Nociceptor Channel TRPM3 gating and pharmacology
伤害感受器通道 TRPM3 门控和药理学的结构基础
  • 批准号:
    10735377
  • 财政年份:
    2023
  • 资助金额:
    $ 41.56万
  • 项目类别:
Deep-learning methods based computational modeling
基于深度学习方法的计算建模
  • 批准号:
    10816248
  • 财政年份:
    2022
  • 资助金额:
    $ 41.56万
  • 项目类别:
Activation and Inhibition Mechanisms of Calcium-Activated Nonselective Cation Channels
钙激活非选择性阳离子通道的激活和抑制机制
  • 批准号:
    10629410
  • 财政年份:
    2022
  • 资助金额:
    $ 41.56万
  • 项目类别:
Activation and Inhibition Mechanisms of Calcium-Activated Nonselective Cation Channels
钙激活非选择性阳离子通道的激活和抑制机制
  • 批准号:
    10503201
  • 财政年份:
    2022
  • 资助金额:
    $ 41.56万
  • 项目类别:
Structural and functional studies of the TRPM2 channel
TRPM2通道的结构和功能研究
  • 批准号:
    10413415
  • 财政年份:
    2019
  • 资助金额:
    $ 41.56万
  • 项目类别:
Structural and functional studies of the TRPM2 channel
TRPM2通道的结构和功能研究
  • 批准号:
    9896879
  • 财政年份:
    2019
  • 资助金额:
    $ 41.56万
  • 项目类别:
Structural and functional studies of the TRPM2 channel
TRPM2通道的结构和功能研究
  • 批准号:
    10386771
  • 财政年份:
    2019
  • 资助金额:
    $ 41.56万
  • 项目类别:
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