Mechanism for Regulating Kainate-Type Glutamate Receptor Activity

红藻氨酸型谷氨酸受体活性调节机制

• 批准号: 7781584
• 负责人: Susumu Tomita
• 金额: $ 41.38万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-12-02 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7781584
• 关键词: AMPA Receptors; Address; Agonist; Ataxia; Autistic Disorder; Biological Models; Biology; Brain; Cell surface; Cells; Characteristics; Complex; DNA; Epilepsy; Excitatory Synapse; Exhibits; GluR6 kainate receptor; Glutamate Receptor; Glutamates; Goals; Injection of therapeutic agent; Integral Membrane Protein; Kainic Acid Receptors; Knockout Mice; Measures; Mediating; Mental Retardation; Mouse Strains; Mus; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Neurons; Neurotransmitters; Oocytes; Pattern; Pharmaceutical Preparations; Physiological; Play; Positioning Attribute; Postsynaptic Membrane; Property; Proteins; Proteomics; Regulation; Role; Schizophrenia; Sensory; Structure; Surface; Synapses; Synaptic Transmission; Synaptic plasticity; System; Transfection; Transgenic Mice; Work; Xenopus laevis; base; drug discovery; experience; genetic regulatory protein; granule cell; insight; kainate; mouse model; nervous system disorder; neural circuit; neurotransmission; novel; postsynaptic; presynaptic; protein expression; public health relevance; receptor; receptor expression; reconstitution; relating to nervous system; research study; trafficking

DESCRIPTION (provided by applicant): The broad goal of this proposal is to understand mechanisms for regulating excitatory synaptic transmission in the brain. Neurological diseases, including mental retardation, autism, epilepsy, and ataxia, are caused by the disruption of neural circuits in the brain. Neural circuits consist of neurons that communicate with each other at synapses through neurotransmitters. The most abundant excitatory neurotransmitter in the brain is glutamate. Glutamate acts on three classes of ionotropic glutamate receptors, AMPA-, NMDA- and kainate-type receptors. AMPA receptors mediate fast synaptic transmission, whereas NMDA receptors modulate synaptic plasticity. However, the physiological roles of kainate receptors remain unclear. We have recently identified a novel transmembrane protein, NETO2 that interacts with the kainate receptor, using an unbiased proteomic screen. In heterologous cells and neurons, NETO2 modulates the channel properties of kainate receptors, and kainate receptors, in turn, modulate NETO2 trafficking. However, there are several unanswered questions to reveal roles of kainate receptors in the brain. 1. How does NETO2/kainate receptor complex assemble and traffic to the cell surface 2. How do NETO2 and kainate receptors modulate each other? 3. How does NETO2/kainate receptor complex mediate the synaptic transmission? In this proposal, we will address these questions to reveal functional roles of kainate receptor/NETO2 complex in the brain. We will identify protein assembling order of kainate receptor/NETO2 complex and mechanisms for surface trafficking using various transgenic mouse model. We will also examine structure and functional analysis of NETO2 and kainate receptors using Xenopus laevis oocyte as a model system. Furthermore, we will reconstitute kainate receptor mediated synaptic transmission in neurons to reveal roles of kainate receptors in excitatory synaptic transmission with electrophysiological experiments. These studies will provide fundamental insights into the mechanisms that regulate synaptic transmission at excitatory synapses regards to roles of neural circuits in the brain. Because potential roles of kainate receptors in several neurological diseases including autism, schizophrenia, epilepsy and altered sensory transduction have been proposed, this work will identify novel targets for drug discovery. PUBLIC HEALTH RELEVANCE: Neurological diseases, including mental retardation, autism, epilepsy, and ataxia, are caused by the disruption of neural circuits in the brain. The broad goal of this proposal is to understand mechanisms for regulating excitatory synaptic transmission in the brain. These studies will provide fundamental insights into the mechanisms that regulate synaptic transmission at excitatory synapses regards to roles of neural circuits in the brain. Because potential roles of kainate receptors in several neurological diseases including autism, schizophrenia, epilepsy and altered sensory transduction have been proposed, this work will identify novel targets for drug discovery.

描述（由申请人提供）：该提案的广泛目标是了解调节大脑兴奋性突触传播的机制。神经系统疾病，包括智力低下，自闭症，癫痫和共济失调，是由大脑中神经回路的破坏引起的。神经回路由神经元组成，这些神经元通过神经递质在突触时相互通信。大脑中最丰富的兴奋性神经递质是谷氨酸。谷氨酸作用于三类离子型谷氨酸受体，AMPA-，NMDA-和Kainate型受体。 AMPA受体介导快速突触传播，而NMDA受体调节突触可塑性。但是，海谷酸酯受体的生理作用尚不清楚。我们最近使用无偏的蛋白质组学筛选确定了一种新型的跨膜蛋白NetO2，该蛋白Neto2与海藻酸盐受体相互作用。在异源细胞和神经元中，NetO2调节海谷酸酯受体的通道特性，而海谷酸酯受体则调节Neto2运输。但是，有几个未解决的问题可以揭示海关系酸盐受体在大脑中的作用。 1。Neto2/Kainate受体复合物如何组装和流量到细胞表面2。Neto2和Kainate受体如何相互调节？ 3。Neto2/Kainate受体复合物如何介导突触传播？在此提案中，我们将解决这些问题，以揭示海藻酸盐受体/NetO2复合物在大脑中的功能作用。我们将使用各种转基因小鼠模型来确定海藻酸盐受体/NetO2复合物的蛋白质组装和表面运输的机制。我们还将使用Xenopus laevis卵母细胞作为模型系统检查Neto2和海藻酸盐受体的结构和功能分析。此外，我们将重建神经元中海藻酸盐受体介导的突触传播，以揭示海藻酸盐受体在兴奋性突触传播中的作用，并通过电生理实验。这些研究将提供对调节兴奋性突触下的突触传播的机制的基本见解。由于已经提出了海藻酸盐受体在几种神经系统疾病中的潜在作用，包括自闭症，精神分裂症，癫痫和感觉转导改变，这项工作将确定药物发现的新靶标。公共卫生相关性：神经系统疾病，包括智力低下，自闭症，癫痫和共济失调，是由大脑中神经回路的破坏引起的。该提案的广泛目标是了解调节大脑兴奋性突触传播的机制。这些研究将提供对调节兴奋性突触下的突触传播的机制的基本见解。由于已经提出了海藻酸盐受体在几种神经系统疾病中的潜在作用，包括自闭症，精神分裂症，癫痫和感觉转导改变，这项工作将确定药物发现的新靶标。