Physiology of potassium channels in retinal glial cells

描述（由申请人提供）：本次更新的中心焦点将是对哺乳动物视网膜中胶质钾、碳酸氢盐和水转运蛋白的大分子组织和功能的分子理解。转运蛋白如何协同工作以协调溶质和水跨胶质细胞膜的转运是神经生物学和视网膜生理学中的一个基本问题。在前一时期，我们已经确定了Kir4.1通道在视网膜细胞外钾浓度调节中的关键作用。本研究旨在进一步阐明视网膜胶质细胞水通道（AQP 4）、钾通道（Kir4.1）和碳酸氢钠共转运体的组成、结构和功能。具体目标如下：1）验证钾和水通道与Muller细胞膜中的肌营养不良蛋白糖蛋白复合物（DGC）相关的假设，2）检验细胞外配体信号传导至DGC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细胞中碳酸氢钠协同转运系统的分子身份，并验证它们是否与DGC相关; 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。钾和水通道以及碳酸氢钠协同转运蛋白在视网膜的钾和酸碱缓冲中起关键作用，并且其亚基组装和大分子组织的缺陷可能与人类疾病有关。因此，对其调控表达至关重要的事件的分子理解对于发展我们在健康和疾病中视网膜功能领域的知识至关重要。

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.