Identifying molecules that modulate auxiliary factors of AMPA receptors

识别调节 AMPA 受体辅助因子的分子

• 批准号: 8769436
• 负责人: Terunaga Nakagawa
• 金额: $ 19.63万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8769436
• 关键词: AMPA Receptors; Adverse effects; Affect; Alzheimer' s Disease; Antibodies; Behavior; Binding; Biological Assay; Brain; Brain region; Cell Line; Cells; Chemicals; Clinical; Cognition; Collection; Dependency; Detection; Diabetes Mellitus; Disease; Drug Targeting; Effectiveness; Evolution; Foundations; Functional disorder; Future; Gated Ion Channel; Genetic; Glutamate Receptor; Homologous Gene; Individual; Ion Channel; Ion Channel Gating; Ketamine; Kinetics; Ligands; Limbic Encephalitis; Major Depressive Disorder; Mediating; Membrane; Mental disorders; Molecular Target; Mus; N-Methylaspartate; Nature; Outcome; Pattern; Pharmaceutical Preparations; Physiological; Play; Positioning Attribute; Potassium Channel; Rasmussen' s Syndrome; Regulation; Role; Shapes; Specificity; Structure; Surface; Symptoms; Synapses; Synaptic Transmission; Synaptic plasticity; Testing; Therapeutic; Time; United States National Institutes of Health; Work; base; channel blockers; clinical effect; clinically relevant; desensitization; drug development; drug use screening; excitatory neuron; improved; inhibitory neuron; mouse model; nervous system disorder; neural circuit; neuronal survival; novel; postsynaptic; protein complex; public health relevance; receptor; receptor expression; response; screening; stable cell line; stargazin; therapeutic development; tool; trafficking

DESCRIPTION: Cognition, behavior, activity of neural circuits, synaptic plasticity, and neuronal survival relate to proper functioning of ligand gated ion channels of the ionotropic glutamate receptors (iGluRs). AMPA-type iGluRs (AMPA-Rs) contribute to the majority of excitatory synaptic transmission in mammalian brain and their dysfunction involves a variety of neurological and psychiatric disorders. For example, positive modulators of AMPA-Rs alleviate major depression disorder (MDD) symptoms, synaptic AMPA-Rs are reduced in mouse models of Alzheimer's disease, and auto-antibodies that bind to AMPA-Rs cause Rasmussen's encephalitis and a subset of limbic encephalitis. In particular, existing drugs for MDD targeting AMPA-Rs have limitations and mechanistically novel AMPA-R modulators are needed for therapeutic development and understanding disease mechanism. AMPA-Rs are protein complexes made of ? and ? subunits. The ? subunits are known as GluA1-4 and construct the tetrameric core of the ligand gated ion channel pore, whereas ? subunits contribute to functional modulation of the receptors without being part of the pore structure. The ? subunits are also known as the auxiliary factors and may be regarded as a set of endogenous modulators of AMPA-Rs developed by nature during evolution. Auxiliary factors modulate the magnitude and shape of postsynaptic responses mediated by AMPA-Rs. Mechanistically, modulating trafficking relates to changing the number and mobility of AMPA-Rs at synapses, whereas altering the gating kinetics of the ion channel will directly modify the time course of membrane depolarization. By changing trafficking and gating parameters influencing postsynaptic currents, auxiliary subunits impact coincident detection and dendritic integration. Ultimately such synaptic modulation is believed to affect the activity of neural circuits and behavior. It is thus conceivable that intervening with endogenous modulators of AMPA-Rs would have strong physiological effects. It is unclear, however, whether ? subunits of iGluR would be effective drug targets for manipulating ligand gated ion channel function. To test this hypothesis, we plan to combine HTS with new cell based assays we developed in order to screen for chemical compounds that specifically act on auxiliary factor dependent modulation of AMPA-Rs. Conventional drugs developed against AMPA-Rs focus on pore forming ? subunits. If new probes are identified from our proposed screening, auxiliary factors of iGluR will become a mechanistically new target for drug development. It is important to note that ? subunits in potassium channels are already established drug targets. New endogenous auxiliary factors of AMPA-Rs are continuously being identified, providing broader spectrum of molecular targets. Each auxiliary factor has distinct expression patters, indicating that targeted drugs will have cel-type specific effects. Using the proposed HTS screening approach, the identification of compounds that modulate AMPA-R activity through interaction with the auxiliary subunits will provide a paradigm shift in developing new drugs against AMPA-Rs, in particular for MDD.

描述：认知、行为、神经回路活动、突触可塑性和神经元存活与离子型谷氨酸受体 (iGluR) 配体门控离子通道的正常功能有关。 AMPA 型 iGluR (AMPA-R) 参与哺乳动物大脑中大部分兴奋性突触传递，其功能障碍涉及多种神经和精神疾病。例如，AMPA-R 的正调节剂可缓解重度抑郁症 (MDD) 症状，阿尔茨海默病小鼠模型中的突触 AMPA-R 减少，与 AMPA-R 结合的自身抗体可导致拉斯穆森脑炎和边缘脑炎的一部分。特别是，现有的针对 AMPA-R 的 MDD 药物存在局限性，需要机制新颖的 AMPA-R 调节剂来进行治疗开发和了解疾病机制。 AMPA-R 是由 ? 组成的蛋白质复合物和 ？亚单位。这 ？亚基称为 GluA1-4，构建配体门控离子通道孔的四聚体核心，而 ?亚基有助于受体的功能调节，但不是孔结构的一部分。这 ？亚基也称为辅助因子，可以被视为自然界在进化过程中形成的一组内源性 AMPA-R 调节剂。辅助因子调节 AMPA-R 介导的突触后反应的幅度和形状。从机制上讲，调节运输涉及改变突触处 AMPA-R 的数量和迁移率，而改变离子通道的门控动力学将直接改变膜去极化的时间过程。通过改变影响突触后电流的运输和门控参数，辅助亚基影响同时检测和树突整合。最终，这种突触调节被认为会影响神经回路的活动和行为。因此可以想象，用 AMPA-R 的内源性调节剂进行干预将产生强烈的生理效应。然而，尚不清楚是否？ iGluR 亚基将成为操纵配体门控离子通道功能的有效药物靶标。为了检验这个假设， 我们计划将 HTS 与我们开发的新的基于细胞的测定相结合，以筛选专门作用于 AMPA-R 的辅助因子依赖性调节的化合物。针对 AMPA-R 开发的传统药物主要关注孔形成？亚单位。如果从我们提出的筛选中鉴定出新的探针，iGluR 的辅助因子将成为药物开发的机械新靶标。值得注意的是？钾通道中的亚基已经是既定的药物靶点。 AMPA-R 的新内源性辅助因子不断被发现，提供了更广泛的分子靶标。每个辅助因子都有不同的表达模式，表明靶向药物将具有细胞类型特异性作用。使用所提出的 HTS 筛选方法，鉴定通过与辅助亚基相互作用调节 AMPA-R 活性的化合物将为开发针对 AMPA-R（特别是 MDD）的新药提供范式转变。