Clustering and Synaptic Targeting of GABA-A Receptors

描述（由申请人提供）： 我们研究的长期目标是解开调节 A型氨基丁酸（GABAA）的聚集和突触后靶向 受体。这些受体是异源五聚体氯离子通道， 介导大脑中大多数抑制性神经传递。GABAA受体亚型 由它们的亚基组成区分，在 区域和细胞水平。GABAA受体的差异定位是 涉及GABA能传递的突触功效的调节， 受体定位的病理变化与衰弱性 癫痫和焦虑等疾病。这些因素和信号通路， 确定受体聚集和定位在很大程度上是未知的， 作为该提案的一部分。大多数GABAA受体亚型是聚集的 在突触后位点通过一种机制，需要g2亚单位和 聚集蛋白质桥蛋白。不同的a亚基可能靶向受体， 不同类型的突触。然而，目前尚不清楚GABAA受体是如何被激活的。 连接桥蛋白和突触下细胞骨架。我们假设 突触定位至少部分由突触后蛋白介导 与G2亚基的胞质蛋白结构域相互作用。为了验证这一 假设我们将定位介导突触后突触后神经元G2亚基结构域， 定位于神经元。体内g2亚基的缺失与 减少GABAA受体通道传导。据推测， 神经发育过程中通道功能的降低可能会导致 GABAA受体簇在g2亚基缺陷神经元中的表达。遗传方法 将用于确定是否需要受体激活 GABAA受体的聚集。最后，新型GABAA受体结合蛋白 与G2或A2亚基相互作用的蛋白质将被分析， 在受体聚集和定位中的作用。这些研究将大大 促进我们对GABA能神经传递调节的理解， 确定新的潜在药物靶点，用于治疗精神和 神经系统疾病，如焦虑和癫痫。

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.