Chloride Cotransporter Function in the Retina

描述(申请人提供)：这项研究项目是一项实验研究，旨在了解阳离子-氯化物共转运体在哺乳动物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部位，已经发现了两种类型的氯离子共转运体，即Na-K-Cl型和K-Cl型共转运体。这些氯离子共转运体调节细胞内的氯离子浓度，使得K-Cl共转运体将氯离子从神经元中排出，而Na-K-Cl共转运体将氯离子输送到细胞内。因此，当氯平衡电位低于静止膜电位时，由于K-Cl共转运体的作用，神经递质GABA使神经元超极化。相反，当由于钠-钾-氯共转运体的作用，氯平衡电位大于静止膜电位时，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会使细胞超极化或去极化。因此，我们将结合电生理、神经化学和解剖学技术来确定氯离子共转运体在视网膜中的作用。一种兔眼球制剂将被用来研究氯离子共转运体在定向选择性和从水平细胞到双极细胞的突触传递中的作用。具体地说，我们将确定钠-钾-氯和钾-氯共转运体在星爆无长突细胞上的不对称分布是否介导了兔开关定向选择性神经节细胞表现出的零向抑制。我们还将确定水平细胞是否在中心双极细胞(和中心神经节细胞)的感受野周围做出贡献，部分是通过GABA介导的直接突触连接，这种突触连接是Na-K-Cl共转运体依赖的，并且是符号保守的。最后，我们将确定氯离子共转运体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的氯离子共转运体功能的了解，将有助于了解人类视网膜的过程和功能障碍，并为视网膜疾病的药物治疗提供基础。

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.