Chloride Cotransporter Function in the Retina

视网膜中的氯离子协同转运蛋白功能

• 批准号: 7126335
• 负责人: STUART C MANGEL
• 金额: $ 29.2万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7126335
• 关键词: GABA receptor; cellular polarity; chloride channels; electrodes; electrophysiology; horizontal cell; immunocytochemistry; laboratory rabbit; membrane transport proteins; retinal bipolar neuron; retinal ganglion; synapses

DESCRIPTION (provided by applicant): This research project is an experimental study that seeks to understand the role of cation-chloride co-transporters in information processing in the mammalian retina. In the retina and elsewhere in the central nervous system, two types of chloride co-transporters, the Na-K-Cl and K-Cl co-transporters, have been identified. These chloride co-transporters regulate the intracellular chloride concentration such that the K-Cl co-transporter extrudes chloride from neurons, whereas the Na-K-Cl co-transporter transports chloride into cells. Thus, the neurotransmitter GABA hyperpolarizes neurons when the chloride equilibrium potential is less than the resting membrane potential due to the action of the K-Cl co-transporter. In contrast, GABA depolarizes neurons when the chloride equilibrium potential is greater than the resting membrane potential due to the action of the Na-K-Cl co-transporter. Thus, depending on the type of chloride co-transporter expressed by a retinal neuron, GABA will either hyperpolarize or depolarize the cell.We will therefore determine the roles of chloride co-transporters in the retina by using a combination of electrophysiological, neurochemical and anatomical techniques. A rabbit eyecup preparation will be used to study the roles of chloride co-transporters in directional selectivity and in synaptic transmission from horizontal cells to bipolar cells. Specifically, we will determine whether an asymmetric distribution of the Na-K-Cl and K-Cl co-transporters on starburst amacrine cells mediates the null direction inhibition exhibited by rabbit ON-OFF directionally-selective ganglion cells. We will also determine whether horizontal cells contribute to the receptive field surround of ON-center bipolar cells (and ON-center ganglion cells) in part by a direct, GABA-mediated synaptic connection that is Na-K-Cl co-transporter-dependent and sign conserving. Finally, we will determine whether and how the development of chloride co-transporter function affects these retinal phenomena.Increased knowledge of chloride co-transporter function in the adult and developing retina will aid in the understanding of human retinal processes and dysfunction, as well as provide the basis for drug therapy for retinal disorders.

描述（由申请人提供）：本研究项目是一项实验研究，旨在了解哺乳动物视网膜中阳离子-氯化物协同转运蛋白在信息处理中的作用。在视网膜和中枢神经系统的其他地方，已经鉴定出两种类型的氯共转运体，Na-K-Cl和K-Cl共转运体。这些氯离子共转运蛋白调节细胞内氯离子浓度，使得K-Cl共转运蛋白将氯离子从神经元中排出，而Na-K-Cl共转运蛋白将氯离子转运到细胞中。因此，当氯平衡电位低于静息膜电位时，由于K-Cl共转运蛋白的作用，神经递质GABA使神经元超极化。相反，当氯平衡电位大于静息膜电位时，由于Na-K-Cl协同转运蛋白的作用，GABA使神经元去极化。因此，根据视网膜神经元表达的氯离子共转运体的类型，GABA将使细胞过度兴奋或去兴奋。因此，我们将通过使用电生理学、神经化学和解剖学技术的组合来确定氯离子共转运体在视网膜中的作用。将使用兔眼杯制剂研究氯共转运蛋白在方向选择性和从水平细胞到双极细胞的突触传递中的作用。具体而言，我们将确定是否星爆无长突细胞介导的零方向抑制兔ON-OFF方向选择性神经节细胞的Na-K-Cl和K-Cl共转运蛋白的不对称分布。我们还将确定水平细胞是否有助于接受场包围的ON-中心双极细胞（和ON-中心神经节细胞）的部分直接，GABA介导的突触连接，是钠-钾-氯共转运蛋白依赖性和符号保存。最后，我们将确定氯离子协同转运蛋白功能的发展是否以及如何影响这些视网膜现象。增加对成人和发育中视网膜中氯离子协同转运蛋白功能的了解将有助于了解人类视网膜过程和功能障碍，并为视网膜疾病的药物治疗提供基础。