Retinal Inhibitory Glycine Receptors

视网膜抑制性甘氨酸受体

• 批准号: 6674875
• 负责人: MALCOLM M SLAUGHTER
• 金额: $ 36.97万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-01 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6674875
• 关键词: NMDA receptors; Urodela; amacrine cells; biophysics; glycine receptors; laboratory rat; neuropharmacology; neurophysiology; neurotransmitter metabolism; protein localization; receptor expression; retina; second messengers

DESCRIPTION (provided by applicant): The glycine receptor is a key inhibitory receptor in the retinal inner plexiform layer. It is found in ~ 40% of amacrine cells. Almost all retinal neurons express glycine receptors. Although glycine performs a number of roles in retina, there has not been a description of the different glycine receptors that may exist. This is in contrast to the two other main fast transmitters in retina, GABA and glutamate. Receptor subtypes for both of these neurotransmitters have been identified, extensively described, and shown to play key, distinct roles in retinal physiology. It is evident that the complexity of synaptic communication in retina is largely due to the diversity of GABA and glutamate receptor subtypes. The same level of complexity is not evident at the glycinergic synapse. A major limitation is that there is very little information about glycine receptor subtypes and poor tools to investigate it. The governing hypothesis of this proposal is that there are multiple glycine receptors in retina. The research plan will be to address the functional and pharmacological differences between glycine receptors in retina, correlating this with the properties of glycine subunits. It is known that at least three types of glycine receptor alpha subunit are expressed in retina and they have different distributions. This implies that there are functional differences between the subunits, warranting the anatomical segregation. This study's long term goal is to define the properties of glycine receptor subtypes as they relate to the function of the synapse and the physiology of vision. One motivation for this study is our finding that there are fast and slow glycine currents in ganglion cells, that these currents have different pharmacological properties, and that they are differentially regulated by second messenger pathways. This suggests that glycine receptor subtypes exist and that their properties are important in specific retinal functions. A first step in understanding glycine receptor diversity is to develop the tools to identify and characterize glycine receptor subtypes. This proposal will use biophysical, pharmacological, and molecular approaches to develop these tools. Two specific aims are to find agonists and antagonists that can distinguish between glycine receptor subtypes. Another is to characterize GABA receptor antagonists which interact with the glycine receptor. These specific aims are a necessary first step in unraveling inhibitory synapses in retina.

描述(申请人提供)：甘氨酸受体是视网膜内丛状层的关键抑制性受体。在约40%的无长突细胞中发现了它。几乎所有的视网膜神经元都表达甘氨酸受体。虽然甘氨酸在视网膜中发挥着许多作用，但目前还没有关于可能存在的不同甘氨酸受体的描述。这与视网膜中另外两种主要的快速递质--GABA和谷氨酸--形成鲜明对比。这两种神经递质的受体亚型已经被识别和广泛描述，并被证明在视网膜生理学中扮演着关键的、不同的角色。可见，视网膜突触通讯的复杂性在很大程度上是由于GABA和谷氨酸受体亚型的多样性。同样的复杂程度在甘氨酸能突触中并不明显。一个主要的限制是关于甘氨酸受体亚型的信息很少，研究它的工具也很少。这一提议的主要假设是，视网膜中存在多种甘氨酸受体。该研究计划将解决视网膜甘氨酸受体之间的功能和药理学差异，并将其与甘氨酸亚单位的特性相关联。目前已知，至少有三种甘氨酸受体α亚单位在视网膜中表达，并且它们的分布不同。这意味着亚基之间存在功能差异，从而保证了解剖学上的分离。这项研究的长期目标是确定甘氨酸受体亚型的特性，因为它们与突触的功能和视觉生理有关。这项研究的动机之一是我们发现神经节细胞中有快的和慢的甘氨酸电流，这些电流具有不同的药理学特性，并且它们受到第二信使通路的不同调节。这表明甘氨酸受体亚型是存在的，它们的性质在特定的视网膜功能中很重要。了解甘氨酸受体多样性的第一步是开发工具来识别和表征甘氨酸受体亚型。这项提议将使用生物物理、药理学和分子方法来开发这些工具。两个具体目标是寻找能够区分甘氨酸受体亚型的激动剂和拮抗剂。另一项是鉴定与甘氨酸受体相互作用的GABA受体拮抗剂。这些特定的目标是解开视网膜中抑制性突触的必要的第一步。