Structural Rearrangements in GABA-A Receptors

GABA-A 受体的结构重排

基本信息

  • 批准号:
    8045411
  • 负责人:
  • 金额:
    $ 31.16万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2008
  • 资助国家:
    美国
  • 起止时间:
    2008-02-15 至 2013-03-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Gamma-aminobutyric acid type A receptors (GABAARs) mediate the majority of synaptic inhibition in the brain and are modulated by a variety of clinically important drugs, such as benzodiazepines, barbiturates, steroids, anesthetics and anti-convulsants. Furthermore, GABAAR mutations have recently been linked to epilepsy. The long-term goal of our research program is to understand the function of the GABAAR in terms of its molecular structure. While recent crystallographic advances have provided valuable structural models of the GABAAR, achieving a full understanding of function also requires knowledge of protein dynamics. GABAARs exist in at least three interconvertible states with distinct functions: inactive/closed, active/open, and desensitized/closed. Very little is known about the protein motions that occur during these structural transitions, which are regulated by neurotransmitter and drug binding. We will use fluorescence recording of site-specific labels in GABAARs expressed in Xenopus oocytes to study the structural rearrangements underlying activation, desensitization, and drug modulation as they occur in real time. We propose to study 1) agonist, partial-agonist and antagonist induced rearrangements, 2) global protein motions, 3) pentobarbital induced structural changes and 4) protein motions during desensitization. The experiments will be interpreted with the aid of recently elucidated atomic- level structures to gain a deeper understanding of the molecular mechanisms underlying the function of GABAARs and their relatives. We cannot hope to predict the actions of a drug or ligand or predict the outcome of a disease-causing mutation in the GABAAR without dissecting the movements in the protein that mediate its function. The research proposed here utilizes an innovative new approach that will enable us to learn how GABAARs function in health and disease states. PUBLIC HEALTH RELEVANCE: The opening and closing of ligand-gated ion channels, which lie in the membranes of nerve cells, regulate information flow throughout the brain. Defects in these channels lead to wide variety of diseases, such as myasthenia, hyperekplexia and epilepsy. These channels are also the targets of a number of clinically used drugs, including muscle relaxants, sedative-hypnotics, anti-convulsants, anxiolytics and anesthetics. We cannot hope to predict the actions of a drug, design safer and more effective drugs, develop better therapeutic strategies or predict the outcome of a disease-causing mutation without knowledge of how these channels work at a molecular level. The research proposed here utilizes an innovative new approach that will increase our understanding of how one type of ion channel, the GABAAR, functions in health and disease and will establish testable hypotheses for elucidating how other related ligand-gated ion channels function.
描述(由申请人提供):γ-氨基丁酸A型受体(GABAAR)介导大脑中的大部分突触抑制,并受多种临床重要药物(如苯二氮卓类、巴比妥类、类固醇、麻醉剂和抗惊厥药)调节。此外,GABAAR突变最近与癫痫有关。我们研究计划的长期目标是了解GABAAR分子结构的功能。虽然最近的晶体学进展提供了有价值的结构模型的GABAAR,实现功能的全面理解还需要蛋白质动力学的知识。GABAAR存在于至少三种具有不同功能的可相互转换的状态中:不活动/关闭,活动/开放和脱敏/关闭。人们对这些结构转变期间发生的蛋白质运动知之甚少,这些结构转变受到神经递质和药物结合的调节。我们将使用爪蟾卵母细胞中表达的GABAAR中位点特异性标记的荧光记录来研究激活、脱敏和药物调节背后的结构重排,因为它们是真实的发生的。我们建议研究1)激动剂,部分激动剂和拮抗剂诱导的重排,2)整体蛋白质运动,3)戊巴比妥诱导的结构变化和4)脱敏过程中的蛋白质运动。这些实验将在最近阐明的原子水平结构的帮助下进行解释,以更深入地了解GABAAR及其亲属功能的分子机制。我们不能指望预测药物或配体的作用,或者预测GABAAR中致病突变的结果,而不解剖介导其功能的蛋白质的运动。本文提出的研究利用了一种创新的新方法,使我们能够了解GABAAR在健康和疾病状态下的功能。公共卫生相关性:位于神经细胞膜中的配体门控离子通道的打开和关闭调节整个大脑的信息流。这些通道的缺陷会导致各种疾病,如肌无力、过度兴奋和癫痫。这些通道也是许多临床使用的药物的靶点,包括肌肉松弛剂、镇静催眠药、抗惊厥药、抗焦虑药和麻醉药。如果我们不知道这些通道在分子水平上是如何工作的,我们就不能指望预测药物的作用、设计更安全、更有效的药物、开发更好的治疗策略或预测致病突变的结果。本文提出的研究利用了一种创新的新方法,将增加我们对一种离子通道GABAAR在健康和疾病中的功能的理解,并将建立可验证的假设,以阐明其他相关的配体门控离子通道的功能。

项目成果

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CYNTHIA M CZAJKOWSKI其他文献

CYNTHIA M CZAJKOWSKI的其他文献

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{{ truncateString('CYNTHIA M CZAJKOWSKI', 18)}}的其他基金

Endogenous Benzodiazepines in the Brain
大脑中的内源性苯二氮卓类药物
  • 批准号:
    9346120
  • 财政年份:
    2016
  • 资助金额:
    $ 31.16万
  • 项目类别:
Structural Rearrangements in GABA-A Receptors
GABA-A 受体的结构重排
  • 批准号:
    7465966
  • 财政年份:
    2008
  • 资助金额:
    $ 31.16万
  • 项目类别:
Structural Rearrangements in GABA-A Receptors
GABA-A 受体的结构重排
  • 批准号:
    7561673
  • 财政年份:
    2008
  • 资助金额:
    $ 31.16万
  • 项目类别:
Structural Rearrangements in GABA-A Receptors
GABA-A 受体的结构重排
  • 批准号:
    7799256
  • 财政年份:
    2008
  • 资助金额:
    $ 31.16万
  • 项目类别:
Structural Rearrangements in GABA-A Receptors
GABA-A 受体的结构重排
  • 批准号:
    8240905
  • 财政年份:
    2008
  • 资助金额:
    $ 31.16万
  • 项目类别:
Benzodiazepine Modulation of GABAa Receptor Kinetics
苯二氮卓类药物对 GABAa 受体动力学的调节
  • 批准号:
    6928524
  • 财政年份:
    2002
  • 资助金额:
    $ 31.16万
  • 项目类别:
Benzodiazepine Modulation of GABAa Receptor Kinetics
苯二氮卓类药物对 GABAa 受体动力学的调节
  • 批准号:
    6661201
  • 财政年份:
    2002
  • 资助金额:
    $ 31.16万
  • 项目类别:
Benzodiazepine Modulation of GABAa Receptor Kinetics
苯二氮卓类药物对 GABAa 受体动力学的调节
  • 批准号:
    6772441
  • 财政年份:
    2002
  • 资助金额:
    $ 31.16万
  • 项目类别:
Benzodiazepine Modulation of GABAa Receptor Kinetics
苯二氮卓类药物对 GABAa 受体动力学的调节
  • 批准号:
    6548551
  • 财政年份:
    2002
  • 资助金额:
    $ 31.16万
  • 项目类别:
Benzodiazepine Modulation of GABAa Receptor Kinetics
苯二氮卓类药物对 GABAa 受体动力学的调节
  • 批准号:
    7061652
  • 财政年份:
    2002
  • 资助金额:
    $ 31.16万
  • 项目类别:

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