Molecular mechanism of ABHD6 enzymatic activity in neurons

神经元ABHD6酶活性的分子机制

基本信息

批准号：
10040363
负责人：
Nephi Stella
金额：
$ 42.76万
依托单位：
UNIVERSITY OF WASHINGTON
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：
2020-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10040363
关键词：
2-arachidonylglycerol 2-arachidonylglycerol signaling Adverse effects Affect Agonist Amino Acids Applications Grants Biological Process Brain Brain Diseases CNR1 gene Cannabinoids Cells Collaborations Crystallization Crystallography Endocannabinoids Enzyme Inhibition Enzymes Epilepsy Escherichia coli Exhibits Fatty Acids Foundations Genetic Glutamate Receptor Glycerol Goals Hydrolase Knowledge Laboratories Learning Length Lipids Measures Molecular Monoacylglycerol Lipases Monoglycerides Mutation Mutation Analysis Neurons Patients Play Proteins Reagent Reporting Research Role Serine Hydrolase Signal Transduction Structure Structure-Activity Relationship System Technology Testing Therapeutic Traumatic Brain Injury Treatment Efficacy Work activity-based protein profiling addiction base cannabinoid receptor endocannabinoid signaling gamma-Aminobutyric Acid inhibitor/antagonist innovation mouse model nervous system disorder novel novel therapeutics postsynaptic postsynaptic neurons pre-clinical presynaptic psychostimulant side effect small molecule small molecule inhibitor spatiotemporal tool

项目摘要

Summary The most abundant endocannabinoids (eCB) in brain, 2-arachidonoyl glycerol (2-AG), is inactivated by two distinct enzymes: monoacylglycerol lipase (MAGL) and hydrolase domain-contain 6 (ABHD6). The selective inhibition of these enzymes increases the net levels of 2-AG in different neuronal compartments, presynaptic and postsynaptic, respectively. Accordingly, selective inhibition of these enzymes induces different spatiotemporal enhancement of 2-AG signaling and distinct or synergistic therapeutic benefits. We recently gathered results showing that ABHD6 hydrolyzes additional monoacylglycerol substrates than 2- AG and that ABHD6 inhibitors increase the net levels of 2-AG only in highly activity neurons, suggesting a novel molecular mechanism. To increase our mechanistic understanding of ABHD6 at the structural and atomic levels, we initiated an effort and have now successfully purified several functional ABHD6 protein constructs ready for structural analysis. Based on this premise, we propose the following two aims that will determine the: Aim 1: Molecular mechanisms of ABHD6 enzymatic activity. Aim 2: Structure function relationship of ABHD6. Completion of the work outline in this new R21 grant proposal will provide a comprehensive understanding of the role of ABHD6 in controlling eCB signaling in brain within the context of neurological diseases. Our long-term goal is to increase our understanding of the role played by ABHD6 in healthy and diseased brain and help develop novel therapeutics that lack the potential for abuse and adverse effects produced by classic cannabinoid agonists.

概括大脑中最丰富的内源性大麻素（ECB），2-芳烃甘油（2-AG），被两个人灭活不同的酶：单酰基甘油脂肪酶（MAGL）和氢酶结构域6（ABHD6）。选择性这些酶的抑制作用增加了不同神经元室中2-AG的净水平，突触前和突触后。根据肯定，对这些酶的选择性抑制会诱导不同的抑制作用 2AG信号传导和独特或协同治疗益处的时空增强。我们最近收集的结果表明，ABHD6水解了超过2--的其他单酰基甘油底物 Ag和ABHD6抑制剂仅在高度活性神经元中增加2-AG的净水平，这表明一种新颖分子机制。为了增加我们对结构和原子水平上ABHD6的机械理解，我们发起了一项努力，现在已经成功纯化了几种功能性ABHD6蛋白构建体准备结构分析。基于此前提，我们提出了以下两个目标，这些目标将确定： AIM 1：ABHD6酶促活性的分子机制。目标2：ABHD6的结构函数关系。在这项新的R21赠款提案中完成工作大纲的完成将提供对 ABHD6在神经系统疾病的背景下控制大脑中欧洲央行信号传导的作用。我们的长期目的是提高我们对ABHD6在健康和解剖大脑中所扮演的角色的理解并帮助开发新的疗法，缺乏经典大麻素产生的滥用和不良影响的潜力激动剂。