Functional Architecture of Glutamate Receptor Channels

谷氨酸受体通道的功能结构

• 批准号: 7558260
• 负责人: LONNIE P WOLLMUTH
• 金额: $ 34.36万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7558260
• 关键词: Acute; Agonist; Alzheimer' s Disease; Architecture; Attenuated; Biological Assay; Brain; Brain Diseases; C-terminal; Cell Death; Cells; Charge; Chimera organism; Chimeric Proteins; Chronic; Coupled; Coupling; Cysteine; Development; Disease; Electrostatics; Elements; Excitatory Synapse; Gated Ion Channel; Glutamate Receptor; Glutamates; Goals; Ion Channel; Kainic Acid Receptors; Laboratories; Learning; Ligand Binding Domain; Ligands; Maintenance; Mediating; Medical; Memory; Mental disorders; Molecular; Molecular Conformation; N-Methylaspartate; Neurodegenerative Disorders; Neurotransmitters; Pain; Parkinson Disease; Perception; Pharmaceutical Preparations; Pharmacologic Substance; Physiological; Physiology; Potassium Channel; Process; Property; Protein Chemistry; Proteins; Proteolysis; Recombinants; Research; Role; Scanning; Schizophrenia; Shapes; Signal Transduction; Site; Site-Directed Mutagenesis; Spinal Cord; Structure; Synapses; Techniques; Work; desensitization; drug development; information processing; insight; novel strategies; protein protein interaction; receptor; receptor function; research study; stargazin; tool

DESCRIPTION (provided by applicant): The long-term objective of my laboratory is to understand the molecular mechanisms underlying signaling in the brain, especially as it relates to higher brain function and disease states. My laboratory focuses mainly on synaptic physiology, specifically those synapses that use glutamate as their neurotransmitter. Glutamate receptors (GluRs) mediate basic information processing in the brain and contribute to the cellular and molecular mechanisms underlying learning and memory, the development and maintenance of cellular connections, and pain transduction and perception. When dysfunctional, GluRs have also been implicated in numerous psychiatric disorders such as schizophrenia as well as in acute and chronic cell death including that associated with various neurodegenerative diseases such as Alzheimer's and Parkinson's disease. The goal of the present proposal is to define GluR structure-function, focusing mainly on the ion channel component of these ligand-gated ion channels. Such information is key to understanding the role of GluRs in brain function as well as the development of drugs that attenuate the cell death they mediate under pathological conditions. This issue will be studied in recombinant GluRs using a variety of techniques including site-directed mutagenesis, cysteine scanning, chimeras, protein chemistry, available crystal structures, fast agonist application, and whole-cell, outside-out patches, and single channel recordings. Specific Aim#1 will study the dynamics of the linker regions coupling the ligand-binding domain to M3, the major transmembrane gating domain. This region represents a critical juncture regulating receptor function and hence sites for modulating receptor dynamics under pathological states. Specific Aim#2 will study the functional and structural contribution of the M4 segment to channel function. All mammalian GluRs subunits have a transmembrane segment, M4, located C-terminal to the core of the ion channel (M1-M3). M4 is a necessary requirement for mammalian GluR function. Defining its contribution to this process will clarify fundamental mechanisms of gating in GluRs. Specific Aim#3 will further pursue issues related to channel gating specifically to desensitization, focusing on electrostatic interactions between the ion channel and the ligand-binding domain. This work will define fundamental principles of GluR structure-function and provide new tools and insights into means to attenuate the cell death GluR mediate under psychiatric states and pathological conditions. PROJECT NARRATIVE: Synapses mediate the transfer of information in the brain and are at the center of how we think, act and learn. Many drugs that have proven successful in the treatment of brain diseases such Alzheimer's and Parkinson's Diseases and mental illness act on synapses so they are a major focus of medical and pharmaceutical research. Our work studies one element -glutamate receptors- found at the most wide spread excitatory synapse in the mammalian brain, trying to define how this element carries out its function and how it might be modulated in disease states.

描述（由申请人提供）：我实验室的长期目标是了解大脑信号传导的分子机制，特别是与高级大脑功能和疾病状态相关的分子机制。我的实验室主要关注突触生理学，特别是那些使用谷氨酸作为神经递质的突触。谷氨酸受体 (GluR) 介导大脑中的基本信息处理，并有助于学习和记忆、细胞连接的发展和维持以及疼痛传导和感知的细胞和分子机制。当功能失调时，GluR 还与许多精神疾病（如精神分裂症）以及急性和慢性细胞死亡有关，包括与各种神经退行性疾病（如阿尔茨海默病和帕金森病）相关的细胞死亡。本提案的目标是定义 GluR 结构功能，主要关注这些配体门控离子通道的离子通道成分。这些信息对于理解 GluR 在大脑功能中的作用以及开发减轻其在病理条件下介导的细胞死亡的药物至关重要。我们将使用多种技术在重组 GluR 中研究这个问题，包括定点诱变、半胱氨酸扫描、嵌合体、蛋白质化学、可用晶体结构、快速激动剂应用以及全细胞、外向斑块和单通道记录。 具体目标#1 将研究将配体结合结构域与主要跨膜门控结构域 M3 偶联的接头区域的动力学。该区域代表调节受体功能的关键节点，因此是在病理状态下调节受体动态的位点。具体目标#2 将研究 M4 片段对通道功能的功能和结构贡献。所有哺乳动物 GluR 亚基都有一个跨膜片段 M4，位于离子通道 (M1-M3) 核心的 C 端。 M4 是哺乳动物 GluR 功能的必要条件。定义其对该过程的贡献将阐明 GluR 门控的基本机制。具体目标#3将进一步研究与脱敏相关的通道门控问题，重点关注离子通道和配体结合域之间的静电相互作用。这项工作将定义 GluR 结构功能的基本原理，并为减轻精神状态和病理条件下 GluR 介导的细胞死亡的方法提供新的工具和见解。 项目叙述：突触介导大脑中的信息传递，是我们思考、行动和学习方式的中心。许多药物已被证明可以成功治疗阿尔茨海默病、帕金森病和精神疾病等脑部疾病，这些药物作用于突触，因此它们是医学和药物研究的主要焦点。我们的工作研究了在哺乳动物大脑中分布最广泛的兴奋性突触中发现的一种元素——谷氨酸受体，试图确定这种元素如何发挥其功能以及它在疾病状态下如何受到调节。