Functional Characterization of an AMPA receptor: GluR3

AMPA 受体的功能表征：GluR3

• 批准号: 7894770
• 负责人: KINNING POON
• 金额: $ 2.1万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7894770
• 关键词: AMPA Receptors; Acute; Adverse effects; Affect; Affinity; Agonist; Alzheimer' s Disease; Amplifiers; Amyotrophic Lateral Sclerosis; Architecture; Behavior; Binding; Cells; Chemical Structure; Chronic; Cleaved cell; Computer software; Data; Detection; Development; Disease; Drug Design; Epilepsy; Event; Family; Future; Gated Ion Channel; Gene Family; Genes; GluR2 subunit AMPA receptor; GluR3 subunit AMPA receptor; Glutamate Agonist; Glutamate Receptor; Glutamates; Huntington Disease; Integral Membrane Protein; Ions; Ischemic Brain Injury; Kinetics; Knowledge; Lead; Length; Ligand Binding Domain; Ligands; Lobe; Measures; Mediating; Methods; Modeling; N-Methylaspartate; Neuraxis; Neurodegenerative Disorders; Neurologic; Nootropic Agents; Normal Range; Orphan; Pathologic Processes; Physiological; Population; Positioning Attribute; Probability; Property; Protein Dynamics; Rattus; Records; Resolution; Series; Structure; Testing; Whole-Cell Recordings; Work; analog; design; kainate; markov model; nervous system disorder; neurotransmission; public health relevance; receptor; receptor function; therapeutic target; willardiine

DESCRIPTION (provided by applicant): Ionotropic glutamate receptors (iGluR's) are ligand gated ion channels that mediate most of the fast excitatory neurotransmission in the central nervous system. Aberrant function of glutamate neurotransmission can lead to neurological disorders. Drugs designed to target glutamate receptors have the potential to treat a number of neurological conditions. Understanding the relationship between the structure, function and dynamics of glutamate receptors is Important for the development of subtype selective pharmacological agents necessary to treat iGluR related disorders. Single channel electrophysiological studies completed on one specific AMPA receptor subtype (GluR3) will provide functional properties of these receptors induced by different agonists and can be used as a model for future studies on other ionotropic glutamate receptors. The first objective of these studies is to characterize the various levels of conductance classes at different ligand concentrations for a full agonist, glutamate, and a group of structurally related partial agonists, the willardiine compounds. The second objective is to model channel behavior and determine kinetic rates that best represent the mode of channel activation. Single channel data will be analyzed with different methods using QuB software that includes a hidden Markov model approach to event detection. The substrate model and kinetic rates will be compared between the full and partial agonists to determine any similarities or differences in channel function. The rat GluR3 gene has been stably transfected into HEK 293 cells and single channel currents will be measured using the cell attached method. Data will be obtained with an EPC7 amplifier and analog low pass filtered with a Bessel filter at a maximum of 10 kHz. By understanding the kinetics of these channels in the context of the structure of the ligand binding domain, new pharmacological agents can be designed to target a specific component of function. PUBLIC HEALTH RELEVANCE: Numerous acute and chronic neurological conditions involve the function of ion permeable glutamate receptors. However, limited knowledge pertaining to the function of these receptors restricts development of new selective pharmacological agents. Understanding various aspects of glutamate receptors, such as structure and function, will lead to better drug design and better treatment for the large population that suffer from neurological conditions.

描述（由申请人提供）：离子型谷氨酸受体（iGluR）是配体门控离子通道，介导中枢神经系统中大部分快速兴奋性神经传递。谷氨酸神经传递功能异常可导致神经系统疾病。旨在靶向谷氨酸受体的药物有可能治疗多种神经系统疾病。了解谷氨酸受体的结构、功能和动力学之间的关系对于开发治疗 iGluR 相关疾病所需的亚型选择性药物非常重要。对一种特定 AMPA 受体亚型 (GluR3) 完成的单通道电生理学研究将提供由不同激动剂诱导的这些受体的功能特性，并可用作其他离子型谷氨酸受体未来研究的模型。这些研究的第一个目标是表征完全激动剂谷氨酸和一组结构相关的部分激动剂威拉丁化合物在不同配体浓度下的不同水平的电导类别。第二个目标是对通道行为进行建模并确定最能代表通道激活模式的动力学速率。将使用 QuB 软件以不同的方法分析单通道数据，其中包括用于事件检测的隐马尔可夫模型方法。将比较完全激动剂和部分激动剂之间的底物模型和动力学速率，以确定通道功能的任何相似性或差异。将大鼠GluR3基因稳定转染至HEK 293细胞中，并使用细胞贴壁法测量单通道电流。数据将通过 EPC7 放大器获得，并使用最大 10 kHz 的贝塞尔滤波器进行模拟低通滤波。通过了解配体结合域结构背景下这些通道的动力学，可以设计新的药物制剂来靶向特定的功能成分。公众健康相关性：许多急性和慢性神经系统疾病都与离子渗透性谷氨酸受体的功能有关。然而，有关这些受体功能的知识有限限制了新的选择性药物的开发。了解谷氨酸受体的各个方面，例如结构和功能，将有助于更好地设计药物，并为大量患有神经系统疾病的人群提供更好的治疗。