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: 8111850
• 负责人: STUART C MANGEL
• 金额: $ 35.63万
• 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 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8111850
• 关键词: Address; Adult; Amacrine Cells; Cations; Cells; Chloride Channels; Chloride Ion; Chlorides; Dark Adaptation; Data; Dendrites; Disease; Distal; Dopamine D1 Receptor; Epilepsy; Equilibrium; Functional disorder; Generations; Glutamates; Goals; Grant; Health; Homeostasis; Human; Interneurons; Knowledge; Lead; Light; Light Adaptations; Maps; Mediating; Membrane Potentials; Molecular; Motion; Nervous System Physiology; Neural Retina; Neuraxis; Neurons; Neurosciences; Neurotransmitters; Nitric Oxide; Oryctolagus cuniculus; Pharmacotherapy; Preparation; Progress Reports; Publishing; Reporting; Research; Research Project Grants; Rest; Retina; Retinal; Retinal Diseases; Role; Signal Transduction; Stimulus; Synapses; Synaptic Transmission; Techniques; Testing; Time; base; gamma-Aminobutyric Acid; ganglion cell; horizontal cell; information processing; neurochemistry; novel; outer plexiform layer; receptive field; research study; response; retinal ischemia; retinal neuron; sodium-potassium chloride cotransporter 2 protein

DESCRIPTION (provided by applicant): This research project is an experimental study that seeks to understand the role of cation-chloride cotransporters in information processing in the retina. In the retina and elsewhere in the central nervous system, two types of chloride cotransporter, the Na-K-2Cl (NKCC) and K-Cl (KCC) cotransporters, have been identified. These chloride cotransporters regulate the intracellular chloride concentration such that KCC extrudes chloride from neurons, whereas NKCC transports chloride into cells. Thus, the neurotransmitter GABA, which opens chloride channels, hyperpolarizes neurons when the chloride equilibrium potential is more negative than the resting membrane potential due to the action of KCC. In contrast, GABA depolarizes neurons when the chloride equilibrium potential is more positive than the resting membrane potential due to the action of NKCC. Thus, depending on the type of chloride cotransporter expressed by a retinal neuron, GABA will either hyperpolarize or depolarize the cell. We will therefore determine the roles of chloride cotransporters in the retina by using a combination of electrophysiological, neurochemical, cell/molecular and anatomical techniques. The rabbit eyecup neural retina preparation will be used to study the roles of chloride cotransporters in directional selectivity and in synaptic transmission in the outer retina. Specifically, we will determine whether chloride cotransporter activity mediates the receptive field surround of bipolar cells and ganglion cells under light- adapted conditions. We will also determine the roles of the chloride cotransporters in the directionally selective light responses of starburst amacrine cells, interneurons that are pre-synaptic to ON-OFF directionally selective ganglion cells. PUBLIC HEALTH RELEVANCE: Increased knowledge of chloride cotransporter activity in the adult retina will aid in the understanding of human retinal function and dysfunction, as well as provide the basis for drug therapy for retinal disorders, such as retinal ischemia, that involve the chloride cotransporters. In addition, increased knowledge of chloride cotransporters may aid in the understanding and treatment of epilepsy and other diseases that involve chloride homeostasis and GABA.

描述（由申请人提供）：该研究项目是一项实验研究，旨在了解阳离子-氯化物协同转运蛋白在视网膜信息处理中的作用。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协同转运蛋白：Na-K-2Cl (NKCC) 和 K-Cl (KCC) 协同转运蛋白。这些氯离子协同转运蛋白调节细胞内氯离子浓度，使得 KCC 将氯离子从神经元中排出，而 NKCC 将氯离子转运到细胞内。因此，当氯离子平衡电位由于 KCC 的作用而比静息膜电位更负时，打开氯离子通道的神经递质 GABA 会使神经元超极化。相反，当由于 NKCC 的作用，氯平衡电位比静息膜电位更正时，GABA 会使神经元去极化。因此，根据视网膜神经元表达的氯协同转运蛋白的类型，GABA 将使细胞超极化或去极化。因此，我们将结合电生理学、神经化学、细胞/分子和解剖学技术来确定氯协同转运蛋白在视网膜中的作用。兔眼杯神经视网膜制备物将用于研究氯协同转运蛋白在方向选择性和外视网膜突触传递中的作用。具体来说，我们将确定氯协同转运蛋白活性是否在光适应条件下介导双极细胞和神经节细胞的感受野周围。我们还将确定氯协同转运蛋白在星爆无长突细胞的定向选择性光反应中的作用，星爆无长突细胞是突触前到开关定向选择性神经节细胞的中间神经元。公共健康相关性：增加对成人视网膜中氯协同转运蛋白活性的了解将有助于了解人类视网膜功能和功能障碍，并为涉及氯协同转运蛋白的视网膜疾病（例如视网膜缺血）的药物治疗提供基础。此外，增加对氯协同转运蛋白的了解可能有助于了解和治疗癫痫和其他涉及氯稳态和 GABA 的疾病。