Regulation of Retinal Gap Junctions

描述(申请人提供)：由缝隙连接介导的电耦合有助于大多数类型的视网膜神经元的信号处理功能。视觉适应过程中缝隙连接的调制对许多神经元的敏感度和感受场特性有深远的影响，并影响哺乳动物视杆细胞环路中的信号流路径。这项研究的长期目标是确定调节视网膜电耦合的机制，并确定哪些调节模式对在不同的电耦合神经回路中观察到的适应过程最重要。以往的研究结果表明，缝隙连接蛋白的磷酸化是调节偶联的关键机制。缝隙连接蛋白35/36(Cx35/36)的磷酸化随着光适应的变化而动态变化，并与耦合直接相关。在这个项目中，我们将研究在AII无长突细胞和光感受器中通过Cx35/36缝隙连接控制耦合的深刻不同的信号机制。我们将确定在这两个系统中连接和解耦缝隙连接的关键分子组件，并研究影响这些不同信号模块组装的因素。这项研究将阐明控制电耦合的基本机制，并揭示在视觉障碍中可能存在缺陷的信号通路。 与公共健康相关：这个项目研究了控制细胞间通信的基本机制，以及视网膜和整个中枢神经系统中神经网络的建立。它将揭示在神经网络功能中扮演重要角色的过程，这些功能影响视觉敏锐度和光线适应、记忆形成和运动协调。这项研究将揭示信号通路，这些通路可能是干预与这些网络功能相关的疾病的目标，包括黄斑变性、癫痫和听力损失。

DESCRIPTION (provided by applicant): Electrical coupling mediated by gap junctions contributes to the signal processing functions of most types of retinal neurons. Modulation of gap junctions during visual adaptation has profound effects on sensitivity and receptive field properties of many neurons and influences the path of signal flow in the mammalian rod circuit. The long-term objectives of this study are to identify the mechanisms that regulate electrical coupling in the retina, and to determine which modes of regulation are most important for the adaptive processes observed in different electrically coupled neural circuits. Previous results have indicated that phosphorylation of gap junction proteins is a critical mechanism to regulate coupling. Phosphorylation of connexin 35/36 (Cx35/36) gap junctions changes dynamically with light adaptation and correlates directly with coupling. In this project, we will examine the profoundly different signaling mechanisms that control coupling through Cx35/36 gap junctions in AII amacrine cells and photoreceptors. We will identify the key molecular components that couple and uncouple the gap junctions in these two systems, and examine the factors that contribute to the assembly of these different signaling modules. This research will shed light on the fundamental mechanisms that control electrical coupling, and reveal signaling pathways that may be defective in visual disorders. PUBLIC HEALTH RELEVANCE: This project examines fundamental mechanisms that control cell-to-cell communication and the establishment of neural networks in the retina and throughout the central nervous system. It will reveal processes that play important roles in neural network functions that affect visual acuity and light adaptation, memory formation, and motor coordination. The study will reveal signaling pathways that may be targets for intervention in disorders linked to these network functions including macular degeneration, epilepsy, and hearing loss.