Physiology of potassium channels in retinal glial cells

描述(申请人提供)：本次更新的中心焦点将放在对哺乳动物视网膜中神经胶质钾、碳酸氢盐和水运输蛋白的大分子组织和功能的分子理解上。在神经生物学和视网膜生理学中，运输蛋白如何协同工作以协调溶质和水的跨神经胶质细胞膜的运输是一个基本问题。在前面的阶段，我们已经确定了Kir4.1通道在调节视网膜细胞外钾浓度中的关键作用。这项研究包括一系列步骤，旨在进一步阐明视网膜神经胶质细胞中水通道(AQP4)、钾通道(Kir4.1)和碳酸氢钠共转运体的组成、结构和功能。其具体目的如下：1)验证钾和水通道与Muller细胞膜上的dystrophin糖蛋白复合体(DGC)相关的假设，2)检验细胞外配体向DGC发出的信号对于Muller细胞中钾和水通道的高度定位表达至关重要的假设，3)确定Muller细胞中碳酸氢钠共转运体系统的分子同一性，并验证它们是否与DGC有关，4)将我们对Kir4.1通道功能的研究扩展到视网膜和视神经星形胶质细胞。钾和水通道和碳酸氢钠共转运体在视网膜的钾和酸碱缓冲中起着关键作用，它们的亚单位组装和大分子结构缺陷可能与人类疾病有关。因此，对其调控表达的核心事件的分子理解对于发展我们在健康和疾病中的视网膜功能领域的知识是至关重要的。

DESCRIPTION (provided by applicant): The central focus of this renewal will be on the molecular understanding of the macromolecular organization and functions of glial potassium, bicarbonate and water transport proteins in the mammalian retina. How transport proteins work together to coordinate the transport of solutes and water across glial cell membranes is a fundamental question in neurobiology and retinal physiology. In the preceding period, we have identified the critical role of Kir4.1 channels in the regulation of extracellular potassium concentration in the retina. This study consists of a series of steps aimed to further elucidate the composition, architecture and functions of water channels (AQP4), potassium channels (Kir4.1) and sodium bicarbonate cotransporters in retinal glia. The specific aims are the following: 1) to verify the hypothesis that potassium and water channels associate with the dystrophin glycoprotein complex (DGC) in Muller cell membranes, 2) to test the hypothesis that extracellular ligand signaling to the DGC is crucial for the highly localized expression of potassium and water channels in Muller cells, 3) determine the molecular identity of sodium bicarbonate cotransporter systems in Muller cells and verify whether they associate with the DGC, 4) extend our studies of the function of Kir4.1 channels to the retinal and optic nerve astrocytes. Potassium and water channels and sodium bicarbonate cotransporters play a critical role in potassium and acid-base buffering in retina and defects in their subunit assembly and macromolecular organization may be implicated in human diseases. The molecular understanding of the events that are central to their regulated expression is therefore essential for developing our knowledge in the area of retinal function in health and in diseases.