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 G-氨基丁酸A型(GABAA)的聚集和突触后靶向性 感受器。这些受体是异五聚氯离子通道，它们 调节大脑中最具抑制性的神经传递。GABAA受体亚型 区别于它们的亚单位组成的是在 区域和细胞层面。GABAA受体的差异定位是 参与GABA能传递和突触效应的调节 受体定位的病理变化与衰弱有关 癫痫和焦虑症等疾病。细胞因子和信号转导途径 确定受体聚集和定位在很大程度上是未知的，应该 被确定为这项提案的一部分。大多数GABAA受体亚型是聚集性的 在突触后部位通过一种需要G2亚单位和 聚集性蛋白吉普林。不同的α亚基可能以受体为靶点 不同类型的突触。然而，目前还不知道GABAA受体是如何 连接到吉普林和突触下的细胞骨架。我们假设 突触定位至少部分由突触后蛋白介导 它们与G2亚基的细胞质蛋白结构域相互作用。为了测试这一点 假设我们将映射介导突触后的G2亚单位结构域 神经元的定位。体内G2亚单位的丢失与 GABAA受体通道电导降低。据推测，这一点 神经发育过程中通道功能的降低可能会导致神经功能丧失 GABAA受体聚集在G2亚单位缺陷神经元中。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，新的GABAA受体结合蛋白 与g2或a2亚基相互作用的基因将根据其 在受体聚集和定位中的作用。这些研究将显著地 提高对GABA能神经递质调控的认识 确定治疗精神和精神障碍的新的潜在药物靶点 神经性疾病，如焦虑症和癫痫。

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.