Alcohol Actions on NMDA Receptor Gating Domains

酒精对 NMDA 受体门控域的作用

• 批准号: 8702031
• 负责人: ROBERT WILLIAM PEOPLES
• 金额: $ 24.4万
• 依托单位: MARQUETTE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8702031
• 关键词: Accounting; Affect; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcoholism; Alcohols; American; Amino Acids; Behavior; Behavioral; Binding; Biological Assay; Brain; Cause of Death; Cell Line; Cells; Cessation of life; Characteristics; Chemicals; Cognition; Coupled; Development; Diagnostic; Ethanol; Glutamate Receptor; Goals; Grant; Individual; Ion Channel; Ion Channel Gating; Kinetics; Knowledge; Laboratories; Learning; Membrane; Modeling; Molecular Models; Motor; Mutation; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Neuroglia; Neurons; Play; Positioning Attribute; Regulation; Research; Role; Scanning; Sensory Process; Site; Societies; Testing; Time; Work; alcohol abuse pharmacotherapy; alcohol effect; alcohol sensitivity; alcohol use disorder; analog; base; cost; economic cost; insight; knock-down; meetings; molecular dynamics; molecular modeling; molecular site; mutant; neurophysiology; new therapeutic target; patch clamp; receptor

DESCRIPTION (provided by applicant): The long term goal of this study is to understand the molecular sites and mechanisms through which alcohol acts to modulate the function of NMDA receptors. Although NMDA receptors are major CNS targets of alcohol action, the molecular sites and mechanisms of action of alcohol on NMDA receptors are still incompletely understood. Alcohol inhibits NMDA receptors by influencing ion channel gating (1;2), and results of recent studies from this and other laboratories point to sites in the membrane-associated (M) domains in the actions of alcohol. Work from this laboratory has identified and characterized amino acid positions in the third and fourth membrane-associated (M) domains of the NMDA receptor NR2A subunit that influence both gating and alcohol sensitivity of the ion channel; at least two of these positions are putative sites of alcohol action. Although the NR2A subunit predominates in the mammalian brain, recent evidence supports the importance of the NR2B subunit in CNS function (3-6) and alcohol action (7-11). In these studies we will use whole-cell, single-channel, and macropatch concentration-jump patch-clamp recording coupled with mutant cycle analysis and kinetic modeling, as well as molecular modeling and molecular dynamics simulations, to test the central hypothesis that alcohol interacts with specific sites in the M3 and M4 domains to modulate NMDA receptor activity via changes in ion channel gating, and that these sites, and the specific mechanism of inhibition, differ among NR2 subunits and different alcohols. These studies will provide the most complete information to date on the mechanism of alcohol action on the NMDA receptor; specifically, they will provide critical insights into both interaction of ethanol and other alcohols with their sites of action on the NMDA receptor, and the influence of ethanol on NMDA receptor kinetics. By identifying sites in the NMDA receptor gating regions that modulate sensitivity to inhibition by alcohol, as well as sites that are likely to directly bind alcohol, these studies will also identify novel therapeutic targets for the treatment of alcohol use disorders. The knowledge gained from these studies could thus provide a basis for a better understanding of the precise role of the NMDA receptor in the neurophysiological and behavioral effects of alcohol, as well as better pharmacotherapy of alcohol abuse and alcoholism.

描述(申请人提供)：这项研究的长期目标是了解酒精调节NMDA受体功能的分子位置和机制。尽管NMDA受体是酒精作用的主要中枢神经系统靶点，但酒精对NMDA受体的分子作用部位和作用机制仍不完全清楚。酒精通过影响离子通道门控来抑制NMDA受体(1；2)，该实验室和其他实验室最近的研究结果指出，酒精作用中的膜相关(M)区域的位置。该实验室的工作已经确定并表征了NMDA受体NR2A亚单位的第三和第四膜相关(M)区域中的氨基酸位置，这些位置影响离子通道的门控和酒精敏感性；其中至少两个位置是酒精作用的推测位置。虽然NR2A亚单位在哺乳动物的大脑中占主导地位，但最近的证据支持NR2B亚单位在中枢神经系统功能(3-6)和酒精作用(7-11)中的重要性。在这些研究中，我们将使用全细胞、单通道和宏膜片浓度跳跃膜片钳记录，结合突变周期分析和动力学模拟，以及分子模拟和分子动力学模拟，来检验酒精与M3和M4结构域的特定位置相互作用通过离子通道门控的变化来调节NMDA受体活性的中心假设，并且这些位置和具体的抑制机制在NR2亚基和不同的酒精之间是不同的。这些研究将提供迄今为止关于酒精对NMDA受体作用机制的最完整的信息；具体地说，它们将为乙醇和其他醇与其在NMDA受体上的作用部位的相互作用以及乙醇对NMDA受体动力学的影响提供关键的见解。通过确定NMDA受体门控区域中调节酒精抑制敏感性的位点，以及可能直接与酒精结合的位点，这些研究还将确定治疗酒精使用障碍的新靶点。因此，从这些研究中获得的知识可以为更好地了解NMDA受体在酒精的神经生理和行为影响中的确切作用以及更好地治疗酒精滥用和酒精中毒提供基础。