Retinal Inhibitory Glycine Receptors

描述（申请人提供）：甘氨酸受体是视网膜内网状层的关键抑制受体。它存在于约40%的无毛细胞中。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起着许多作用，但还没有对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和谷氨酸形成对比。这两种神经递质的受体亚型已经被确定，广泛描述，并显示在视网膜生理学中发挥关键的、独特的作用。很明显，视网膜突触通讯的复杂性主要是由于GABA和谷氨酸受体亚型的多样性。这种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，研究它的工具也很差。这个提议的主导假设是视网膜中有多个甘氨酸受体。研究计划将解决视网膜中甘氨酸受体之间的功能和药理学差异，并将其与甘氨酸亚基的性质联系起来。已知至少有三种类型的甘氨酸受体α亚基在视网膜中表达，它们具有不同的分布。这意味着亚基之间存在功能差异，从而保证了解剖上的分离。本研究的长期目标是确定甘氨酸受体亚型的特性，因为它们与突触功能和视觉生理学有关。这项研究的一个动机是我们发现在神经节细胞中存在快速和缓慢的甘氨酸电流，这些电流具有不同的药理特性，并且它们受到第二信使途径的不同调节。这表明存在甘氨酸受体亚型，它们的特性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。本提案将使用生物物理、药理学和分子方法来开发这些工具。两个特定的目的是找到可以区分甘氨酸受体亚型的激动剂和拮抗剂。另一个是表征与甘氨酸受体相互作用的GABA受体拮抗剂。这些特定的目标是揭开视网膜中抑制性突触的必要的第一步。

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.