Clustering and Synaptic Targeting of GABA-A Receptors

GABA-A 受体的聚类和突触靶向

• 批准号: 6782548
• 负责人: BERNHARD LUSCHER
• 金额: $ 27.92万
• 依托单位: PENNSYLVANIA STATE UNIVERSITY, THE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-01 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6782548
• 关键词: GABA receptor; binding proteins; cytoskeleton; electrophysiology; gene targeting; genetically modified animals; immunocytochemistry; immunofluorescence technique; immunoprecipitation; laboratory mouse; membrane transport proteins; neural transmission; neurons; protein localization; protein protein interaction; protein structure; protein structure function; receptor expression; synapses; tissue /cell culture; transfection

DESCRIPTION (provided by applicant): The long-term goal of our research is to unravel the mechanism regulating the clustering and postsynaptic targeting of g-aminobutyric acid type A (GABAA) receptors. These receptors are hetero-pentameric chloride channels and they mediate most inhibitory neurotransmission in the brain. GABAA receptor subtypes distinguished by their subunit composition are differentially expressed at the regional and cellular level. Differential localization of GABAA receptors is implicated in regulation of synaptic efficacy of GABAergic transmission and pathological changes in receptor localization are implicated in debilitating disorders such as epilepsy and anxiety. The factors and signaling pathways that determine receptor clustering and localization are largely unknown and shall be identified as part of this proposal. Most GABAA receptor subtypes are clustered at postsynaptic sites by a mechanism that requires the g2 subunit and the clustering protein gephyrin. Different a subunits might target receptors to different types of synapses. However, it is not known how GABAA receptors are linked to gephyrin and to the subsynaptic cytoskeleton. We hypothesize that synaptic localization is mediated at least in part by postsynaptic proteins that interact with cytoplasmic protein domains of the g2 subunit. To test this hypothesis we will map g2 subunit domains that mediate postsynaptic localization in neurons. Loss of the g2 subunit in vivo is associated with a reduced GABAA receptor channel conductance. It has been postulated that this reduced channel function during neural development might contribute to loss of GABAA receptor clusters in g2 subunit deficient neurons. Genetic approaches will be used to determine whether receptor activation is required for clustering of GABAA receptors. Finally, novel GABAA receptor binding proteins that interact with the g2 or a2 subunits will be analyzed with respect to their role in receptor clustering and localization. These studies will significantly advance our understanding of the regulation of GABAergic neurotransmission and identify new potential drug targets for the treatment of mental and neurological disorders such as anxiety and epilepsy.

描述（由申请人提供）： 我们研究的长期目标是揭示调节机制 A 型氨基丁酸 (GABAA) 的聚类和突触后靶向 受体。这些受体是异五聚氯离子通道，它们 介导大脑中大多数抑制性神经传递。 GABAA 受体亚型 根据其亚基组成进行区分，差异表达于 区域和细胞水平。 GABAA 受体的差异定位是 参与调节 GABA 能传递的突触功效 受体定位的病理变化与衰弱有关 癫痫和焦虑症等疾病。影响因素和信号通路 确定受体聚类和定位在很大程度上是未知的，应 确定为本提案的一部分。大多数 GABAA 受体亚型呈簇状 在突触后位点通过需要 g2 亚基和 聚集蛋白 gephyrin。不同的亚基可能靶向受体 不同类型的突触。然而，GABAA受体如何作用尚不清楚。 与 gephyrin 和突触下细胞骨架相连。我们假设 突触定位至少部分由突触后蛋白介导 与 g2 亚基的细胞质蛋白结构域相互作用。为了测试这个 假设我们将绘制介导突触后的 g2 亚基结构域 神经元中的定位。体内 g2 亚基的丢失与 降低 GABAA 受体通道电导。据推测，这 神经发育过程中通道功能的减少可能会导致神经发育过程中通道功能的丧失 g2 亚基缺陷神经元中的 GABAA 受体簇。遗传方法 将用于确定是否需要受体激活 GABAA 受体聚集。最后，新型 GABAA 受体结合蛋白 将分析与 g2 或 a2 亚基相互作用的 在受体聚集和定位中发挥作用。这些研究将显着 增进我们对 GABA 能神经传递调节的理解 确定治疗精神和疾病的新的潜在药物靶点 神经系统疾病，例如焦虑和癫痫。