Mechanisms of RyR1 Modulation by General Anesthetics

全身麻醉药调节 RyR1 的机制

基本信息

  • 批准号:
    10335174
  • 负责人:
  • 金额:
    $ 43.78万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-01-10 至 2023-12-31
  • 项目状态:
    已结题

项目摘要

Description: The skeletal muscle ryanodine receptor (RyR1) is a critical regulator of cellular calcium to facilitate excitation contraction coupling. Mutations in this receptor underlie a number of serious disorders, one of which is called malignant hyperthermia (MH). MH typically occurs unexpectedly during a general anesthetic, and can be fatal. The intramolecular mechanism by which anesthetics modulate this receptor, or even if they interact directly with RyR1, is completely unknown. For both wild type and MH mutant (R615C) porcine RyR1, we will use photolabeling technology to determine whether and where two volatile anesthetics, isoflurane and sevoflurane, bind (Aim 1); then reconcile these sites with the structure and structural changes using cryo-electron microscopy (Aim 2). We will determine their single-channel effects on ion transit using planar lipid bilayer electrophysiology (Aim 3). Finally, we will gauge relative binding affinity among the expected multiple sites and which of these are most likely to be linked to functional effects, using sophisticated computational approaches (equilibrium molecular dynamics and alchemical free energy perturbation, Aim 4). We will test the effect of site-directed and natural mutations on binding affinity in individual sites, which will then be iteratively tested by experiment in Aims 1 and 3. The included preliminary data lends confidence for a successful outcome in each aim, and also has yielded surprising results in the case of propofol, an injectable general anesthetic. The RyR1 is a challenging target due to its size and complexity, but the technologies (photolabeling, mass spectrometry, cryo-electron microscopy, planar bilayer electrophysiology, molecular dynamics) have matured to a point where this multidisciplinary campaign has a very high probability of revealing the intramolecular mechanism of anesthetic modulation .
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项目成果

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Roderic G Eckenhoff其他文献

Roderic G Eckenhoff的其他文献

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{{ truncateString('Roderic G Eckenhoff', 18)}}的其他基金

Relationship between CNS Tau burden and perioperative neurocognitive disorder
CNS Tau负荷与围手术期神经认知障碍的关系
  • 批准号:
    10232053
  • 财政年份:
    2020
  • 资助金额:
    $ 43.78万
  • 项目类别:
Mechanisms of RyR1 Modulation by General Anesthetics
全身麻醉药调节 RyR1 的机制
  • 批准号:
    10544782
  • 财政年份:
    2020
  • 资助金额:
    $ 43.78万
  • 项目类别:
Mechanisms of RyR1 Modulation by General Anesthetics
全身麻醉药调节 RyR1 的机制
  • 批准号:
    10084299
  • 财政年份:
    2020
  • 资助金额:
    $ 43.78万
  • 项目类别:
Inhaled Anesthetic Binding: Features and Location
吸入麻醉剂绑定:特征和位置
  • 批准号:
    7740024
  • 财政年份:
    2009
  • 资助金额:
    $ 43.78万
  • 项目类别:
High throughput screening of a general anesthetic binding site
全身麻醉剂结合位点的高通量筛选
  • 批准号:
    7761812
  • 财政年份:
    2009
  • 资助金额:
    $ 43.78万
  • 项目类别:
Anesthetics and Alzheimer's Disease
麻醉药和阿尔茨海默病
  • 批准号:
    7663949
  • 财政年份:
    2008
  • 资助金额:
    $ 43.78万
  • 项目类别:
Anesthetics and Alzheimer's Disease
麻醉药和阿尔茨海默病
  • 批准号:
    8067038
  • 财政年份:
    2008
  • 资助金额:
    $ 43.78万
  • 项目类别:
Anesthetics and Alzheimer's Disease
麻醉药和阿尔茨海默病
  • 批准号:
    7525564
  • 财政年份:
    2008
  • 资助金额:
    $ 43.78万
  • 项目类别:
Anesthetics and Alzheimer's Disease
麻醉药和阿尔茨海默病
  • 批准号:
    7844873
  • 财政年份:
    2008
  • 资助金额:
    $ 43.78万
  • 项目类别:
Anesthetics and Alzheimer's Disease
麻醉药和阿尔茨海默病
  • 批准号:
    8286955
  • 财政年份:
    2008
  • 资助金额:
    $ 43.78万
  • 项目类别:

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    10799162
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    2022
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