Structural Requirements for Benzodiazepine Modulation of GABA-A Receptors
GABA-A 受体的苯二氮卓类调节的结构要求
基本信息
- 批准号:7406196
- 负责人:
- 金额:$ 4.96万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2007
- 资助国家:美国
- 起止时间:2007-09-30 至 2010-09-29
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectAffinityAnti-Anxiety AgentsAnticonvulsantsAntipsychotic AgentsAnxietyBarbituratesBenzodiazepinesBindingBinding SitesBrainClassCoupledCouplingCysteineDNA Sequence RearrangementDataDiseaseDisulfidesDrug usageElectrodesElementsEpilepsyEthanolFlunitrazepamGABA ReceptorGABA-A ReceptorGated Ion ChannelHomology ModelingInvestigationKnowledgeLigandsLinkMeasuresMediatingMental DepressionMethodsMovementMuscle relaxantsMutateMutationNeural InhibitionNeuraxisOccupationsPharmaceutical PreparationsPropertyRangeReceptor ActivationResearchSchizophreniaSiteSite-Directed MutagenesisSleepTestingTherapeuticbarbituric acid saltdesigngamma-Aminobutyric Acidimprovedinsightneurotransmissionpatch clampradioligandreceptorresearch studyresponsevoltage clampzolpidem
项目摘要
DESCRIPTION (provided by applicant): Gamma-aminobutyric acid type A receptors (GABARs) are ligand-gated ion channels that mediate the majority of rapid inhibitory neurotransmission in the central nervous system. Alterations in GABAR-mediated neural inhibition have been linked to several disorders including epilepsy, schizophrenia, anxiety, and depression. Several clinically important drugs including benzodiazepines (BZDs), barbiturates, anethestics, and ethanol exert their therapeutic actions by modulating the GABA-mediated current of the GABAR. However, the exact mechanism by which these modulators alter GABA-activation of the receptor is still debated. Specifically, the structural elements underlying BZD positive and negative modulation remain unknown. The main objective of this proposal is to determine how BZDs with different functional (positive, negative, and zero modulators) and structural properties (classical and non-classical) modulate the GABAR. I will use several experimental approaches including site-directed mutagenesis, two-electrode voltage clamp, cysteine accessibility, disulfide trapping, and radioligand binding to test the hypothesis that a specific region in the receptor, Loop F of the gamma2 subunit, contributes to BZD efficacy and is important for coupling BZD binding to modulation of GABA-mediated current. Additional studies using receptors composed of tethered tandem subunits, patch clamping, and cysteine accessibility will provide insight into the mechanism by which BZDs relay their information to the GABA binding sites. Benzodiazepines are one of the most commonly prescribed classes of drugs and are used as anxiolytics, anticonvulsants, sleep aids, muscle relaxants, and antipsychotics. Research proposed in this study will enhance our understanding of the structural elements underlying the selective affinity and efficacy of benzodiazepines, and will be instrumental in the rational design of new, more effective drugs for the treatment of disorders ranging from anxiety to epilepsy.
描述(由申请人提供):γ-氨基丁酸A型受体(GABAR)是配体门控离子通道,介导中枢神经系统中的大多数快速抑制性神经传递。GABAR介导的神经抑制的改变与包括癫痫、精神分裂症、焦虑和抑郁在内的几种疾病有关。几种临床上重要的药物,包括苯二氮卓类(BZD)、巴比妥类药物、麻醉剂和乙醇,通过调节GABA介导的GABAR电流发挥其治疗作用。然而,这些调节剂改变GABA受体激活的确切机制仍有争议。具体而言,BZD正和负调节的结构要素仍然未知。本提案的主要目的是确定具有不同功能(正、负和零调节剂)和结构特性(经典和非经典)的BZD如何调节GABAR。我将使用几种实验方法,包括定点诱变,双电极电压钳,半胱氨酸可及性,二硫键捕获和放射性配体结合,以测试受体中的特定区域,环F的γ 2亚基,有助于BZD疗效的假设,是重要的耦合BZD结合GABA介导的电流的调制。使用由栓系串联亚基、膜片钳和半胱氨酸可及性组成的受体的其他研究将深入了解BZD将其信息传递给GABA结合位点的机制。苯二氮卓类药物是最常用的处方类药物之一,用作抗焦虑药、抗惊厥药、助眠药、肌肉松弛药和抗精神病药。本研究中提出的研究将提高我们对苯二氮卓类药物的选择性亲和力和疗效的结构要素的理解,并将有助于合理设计新的,更有效的药物,用于治疗从焦虑到癫痫的疾病。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Susan M Hanson其他文献
Susan M Hanson的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Susan M Hanson', 18)}}的其他基金
Structural Requirements for Benzodiazepine Modulation of GABA-A Receptors
GABA-A 受体的苯二氮卓类调节的结构要求
- 批准号:
7502651 - 财政年份:2007
- 资助金额:
$ 4.96万 - 项目类别:
相似海外基金
RII Track-4:NSF: From the Ground Up to the Air Above Coastal Dunes: How Groundwater and Evaporation Affect the Mechanism of Wind Erosion
RII Track-4:NSF:从地面到沿海沙丘上方的空气:地下水和蒸发如何影响风蚀机制
- 批准号:
2327346 - 财政年份:2024
- 资助金额:
$ 4.96万 - 项目类别:
Standard Grant
BRC-BIO: Establishing Astrangia poculata as a study system to understand how multi-partner symbiotic interactions affect pathogen response in cnidarians
BRC-BIO:建立 Astrangia poculata 作为研究系统,以了解多伙伴共生相互作用如何影响刺胞动物的病原体反应
- 批准号:
2312555 - 财政年份:2024
- 资助金额:
$ 4.96万 - 项目类别:
Standard Grant
How Does Particle Material Properties Insoluble and Partially Soluble Affect Sensory Perception Of Fat based Products
不溶性和部分可溶的颗粒材料特性如何影响脂肪基产品的感官知觉
- 批准号:
BB/Z514391/1 - 财政年份:2024
- 资助金额:
$ 4.96万 - 项目类别:
Training Grant
Graduating in Austerity: Do Welfare Cuts Affect the Career Path of University Students?
紧缩毕业:福利削减会影响大学生的职业道路吗?
- 批准号:
ES/Z502595/1 - 财政年份:2024
- 资助金额:
$ 4.96万 - 项目类别:
Fellowship
Insecure lives and the policy disconnect: How multiple insecurities affect Levelling Up and what joined-up policy can do to help
不安全的生活和政策脱节:多种不安全因素如何影响升级以及联合政策可以提供哪些帮助
- 批准号:
ES/Z000149/1 - 财政年份:2024
- 资助金额:
$ 4.96万 - 项目类别:
Research Grant
感性個人差指標 Affect-X の構築とビスポークAIサービスの基盤確立
建立个人敏感度指数 Affect-X 并为定制人工智能服务奠定基础
- 批准号:
23K24936 - 财政年份:2024
- 资助金额:
$ 4.96万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
How does metal binding affect the function of proteins targeted by a devastating pathogen of cereal crops?
金属结合如何影响谷类作物毁灭性病原体靶向的蛋白质的功能?
- 批准号:
2901648 - 财政年份:2024
- 资助金额:
$ 4.96万 - 项目类别:
Studentship
ERI: Developing a Trust-supporting Design Framework with Affect for Human-AI Collaboration
ERI:开发一个支持信任的设计框架,影响人类与人工智能的协作
- 批准号:
2301846 - 财政年份:2023
- 资助金额:
$ 4.96万 - 项目类别:
Standard Grant
Investigating how double-negative T cells affect anti-leukemic and GvHD-inducing activities of conventional T cells
研究双阴性 T 细胞如何影响传统 T 细胞的抗白血病和 GvHD 诱导活性
- 批准号:
488039 - 财政年份:2023
- 资助金额:
$ 4.96万 - 项目类别:
Operating Grants
How motor impairments due to neurodegenerative diseases affect masticatory movements
神经退行性疾病引起的运动障碍如何影响咀嚼运动
- 批准号:
23K16076 - 财政年份:2023
- 资助金额:
$ 4.96万 - 项目类别:
Grant-in-Aid for Early-Career Scientists