Regulation of Retinal Gap Junctions

神经系统中的突触交流是由两大类突触完成的，化学突触 和电力，它们以不同的方式运行。电突触是由神经元之间的缝隙连接形成的 并允许电流在电池之间直接传递，提供快速且经常是双向的 沟通。这种通讯的大小的细胞控制提炼了局部和远程神经 网络的功能，是网络可塑性的重要组成部分。电突触可塑性发挥着重要作用 在脊椎动物视网膜的感觉适应中起着特别重要的作用，其中一些偶联的变化 网络超过了一个数量级。 这一既定研究项目的长期目标是阐明控制 电突触的可塑性。在最近的工作中，我们发现了肌动蛋白之间的密切关系 细胞骨架与连接蛋白36(Cx36)缝隙连接的偶联功能控制。这似乎整合了 兴奋性和抑制性信号的主要成分以及在这些模式之间的切换。这个项目 将使用细胞培养和小鼠视网膜模型系统相结合的方式来研究这些联系。我们将测试 关于Cx36功能偶联调控的三个具体假说如下：(1)信号蛋白 调节Cx36偶联的复合体与肌动蛋白细胞骨架有关。使用邻近标记和 定量蛋白质组学技术，我们将确定参与调控Cx36的信号成分 耦合。我们将进一步研究这些组件在Cx36附近的动态变化 监管信号。(2)Cx36的磷酸化改变了其与信号成分的联系。我们会 研究Cx36某些残基的磷酸化如何调节某些信号的关联 组件。(3)RhoA和CDC42信号通路调节功能可塑性。我们将调查如何 控制细胞骨架重塑的通路影响Cx36的偶联。 拟议的研究将阐明控制电突触功能可塑性的核心机制。 对这些机制的了解将不仅为视觉适应的控制提供大量的洞察力 视网膜中的过程，也是整个大脑中电突触的可塑性。这将允许 开发针对缝隙连接起作用的疾病的靶向治疗方法。

Synaptic communication in the nervous system is accomplished by two major classes of synapses, chemical and electrical, which operate in different ways. Electrical synapses are formed by gap junctions between neurons and allow passage of electrical current directly between cells, providing fast and often bi-directional communication. Cellular control of the magnitude of this communication refines local and long-range neural network functions, and is an important component of network plasticity. Electrical synapse plasticity plays a particularly important role in sensory adaptation in the vertebrate retina, where changes in coupling of some networks exceed an order of magnitude. The long-term goals of this established research project are to elucidate the mechanisms that control plasticity of electrical synapses. In recent work, we have discovered an intimate relationship between the actin cytoskeleton and functional control of coupling in Connexin 36 (Cx36) gap junctions. This appears to integrate the main components of excitatory and inhibitory signaling and switching between those modes. This project will investigate those links, using a combination of cell culture and mouse retina model systems. We will test three specific hypotheses about regulation of Cx36 functional coupling in the following ways: (1) Signaling protein complexes that regulate Cx36 coupling are associated with the actin cytoskeleton. Using proximity labeling and quantitative proteomic techniques, we will identify signaling components involved in the regulation of Cx36 coupling. We will further investigate the dynamic changes in proximity of these components to Cx36 during regulatory signaling. (2) Phosphorylation of Cx36 alters its association with signaling components. We will investigate how phosphorylation of certain residues of Cx36 regulates the association of some signaling components. (3) RhoA and Cdc42 signaling pathways modulate functional plasticity. We will investigate how pathways that control cytoskeletal remodeling influence coupling of Cx36. The proposed studies will elucidate mechanisms central to control of electrical synapse functional plasticity. Knowledge of these mechanisms will provide a great deal of insight not only into the control of visual adaptation processes in the retina, but also electrical synapse plasticity throughout the brain. This will allow the development of targeted therapies for disorders in which gap junctions play a role.