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，神经回路的活性，突触可塑性和神经元存活与离子型谷氨酸受体（Iglurs）的配体裂隙离子通道的正确功能有关。 AMPA型iGlurs（AMPA-RS）在哺乳动物大脑中的大多数兴奋性突触传播及其功能障碍都涉及多种神经系统和精神疾病。例如，AMPA-RS的阳性调节剂减轻了严重抑郁症（MDD）症状，在阿尔茨海默氏病的小鼠模型中降低了突触AMPA-RS，并且与AMPA-RS结合的自身抗体导致Rasmussen的脑炎和incephality的自身抗体。特别是，现有用于MDD靶向AMPA-R的药物具有局限性，并且需要机械新颖的AMPA-R调节剂来治疗性发育和理解疾病机制。 AMPA-RS是由蛋白质复合物制成的吗？和 ？亚基。这 ？亚基被称为glua1-4，并构建了配体门控离子通道孔的四聚核，而？亚基有助于对受体的功能调节，而不是孔结构的一部分。这 ？亚基也被称为辅助因子，可以被视为在进化过程中自然发展的AMPA-RS的一组内源性调节剂。辅助因子调节由AMPA-RS介导的突触后反应的大小和形状。机械上，调节运输与更改突触处AMPA-RS的数量和迁移率有关，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，辅助亚基会影响一致的检测和树突一体化。最终，这种突触调节被认为会影响神经回路和行为的活性。因此，可以想象，与AMPA-RS的内源调节剂进行干预会产生强大的生理作用。但是，是否不清楚？ iglur的亚基将是操纵配体门控离子通道功能的有效药物靶标。为了检验这一假设， 我们计划将HTS与我们开发的新基于细胞的测定法相结合，以筛选出专门针对AMPA-RS辅助因子依赖性调制的化学化合物。针对AMPA-RS开发的常规药物专注于孔形成？亚基。如果从我们提出的筛查中确定了新的探针，则Iglur的辅助因素将成为药物开发的机械新目标。重要的是要注意吗？钾通道中的亚基已经建立了药物靶标。 AMPA-RS的新内源性辅助因子正在连续鉴定，从而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CEL类型的特定作用。使用拟议的HTS筛选方法，通过与辅助亚基相互作用来调节AMPA-R活性的化合物将在开发针对AMPA-RS的新药物（尤其是MDD）中提供范式转移。