STRUCTURE AND FUNCTION RELATIONSHIP OF CONE CYCLIC NUCLEOTIDE-GATED CHANNEL

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 视锥细胞环核苷酸门控（CNG）通道对于中心视觉、色觉和视敏度至关重要。 该通道由CNGA 3和CNGB 3亚基组成。 CNGA 3是离子传导亚基，而CNGB 3被称为调节剂。 视锥细胞CNG通道的突变与色盲、进行性视锥细胞营养不良和早发性黄斑变性有关。然而，我们的理解，这一渠道和锥缺陷的发病机制是非常有限的。 这主要是由于调查视杆细胞占主导地位的哺乳动物视网膜中的视锥系统的困难。 我们建议使用小鼠模型来研究锥体CNG通道。 我们的工作表明，在转录因子神经视网膜亮氨酸拉链（Nrl基因敲除小鼠）的锥显性小鼠系缺陷是一个有用的模型，研究锥CNG通道。 使用Nrl敲除小鼠，我们证明天然锥CNG通道是包含CNGA 3和CNGB 3的异源四聚体复合物。 通过使用CNGB 3敲除小鼠，我们显示CNGB 3在视锥细胞功能和存活中的重要作用。 CNGB 3基因敲除小鼠显示视锥细胞功能降低并发生视锥细胞变性。 CNGA 3-Nrl双基因敲除小鼠对研究视锥细胞变性机制具有重要价值。 使用该小鼠系，我们发现氧化应激可能在通道缺陷导致的视锥细胞变性中起潜在作用。 我们研究的长期目标是阐明通道缺陷导致的视锥细胞缺陷的发病机制和细胞机制，目的是确定潜在的视锥细胞疾病的治疗干预措施。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The cone cyclic nucleotide-gated (CNG) channel is essential for central and color vision and visual acuity. This channel is composed of CNGA3 and CNGB3 subunits. CNGA3 is the ion-conducting subunit while CNGB3 is known as a modulator. Mutations in cone CNG channel are associated with achromatopsia, progressive cone dystrophy and early-onset macular degeneration. However, our understanding of this channel and pathogenesis of cone defects is very limited. This is primarily due to the difficulty of investigating the cone system in a rod dominant mammalian retina. We proposed to study cone CNG channel using mouse models. Our work shows that the cone dominant mouse line deficient in the transcription factor neural retina leucine zipper (Nrl knockout mice) is a useful model to study cone CNG channel. Using Nrl knockout mice we demonstrate that the native cone CNG channel is a heterotetrameric complex comprising both CNGA3 and CNGB3. By using CNGB3 knockout mice, we show the essential role of CNGB3 in cone function and survival. CNGB3 knockout mice show decreased cone function and develop cone degeneration. We also show that the CNGA3-Nrl double knockout mouse line is valuable to study the mechanism of cone degeneration. Using this mouse line we found that oxidative stress may play a potential role in cone degeneration resulting from channel deficiency. The long-term goal of our research is to elucidate the pathogenesis and cellular mechanism of the cone defects resulting from channel deficiency with the objective of identifying potential therapeutic interventions for the cone diseases.