Structural landscape of photoreceptor synapses

感光器突触的结构景观

• 批准号: 10707351
• 负责人: Kirill A. Martemyanov
• 金额: $ 48.3万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-30 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10707351
• 关键词: Architecture; Biochemical; Biochemistry; Bipolar Neuron; Blindness; Brain; Cell Adhesion; Cell Adhesion Molecules; Cells; Cellular biology; Cessation of life; Collaborations; Communication; Complex; Cone; Cone dystrophy; Cryoelectron Microscopy; Dedications; Disease; Elements; Functional disorder; G-Protein-Coupled Receptors; GTP-Binding Protein Regulators; Glean; Glutamates; Goals; Human; India; International; Laboratories; Light; Membrane Potentials; Molecular; Molecular Structure; Mutation; Neurons; Neurotransmitter Receptor; Neurotransmitters; Night Blindness; Ocular Pathology; Orphan; Photons; Photoreceptors; Phototransduction; Play; Presynaptic Terminals; Proteins; RGS Proteins; Regulation; Research; Resolution; Retina; Retinal Cone; Retinal Diseases; Rod; Role; Sensory; Signal Transduction; Site-Directed Mutagenesis; Structure; Synapses; Synaptic Cleft; Synaptic Receptors; Synaptic Transmission; System; Vertebrate Photoreceptors; Vision; Work; comorbidity; experimental study; extracellular; follow-up; improved; interdisciplinary approach; macromolecular assembly; novel therapeutic intervention; postsynaptic; presynaptic; programs; protein protein interaction; receptor; reconstitution; response; scaffold; success; synaptic function; therapy development; transmission process; virtual; visual processing

PROJECT SUMMARY Rod and cone photoreceptors are indispensable for our vision. Their death or dysfunction is an underlying cause for a vast majority of blinding retina conditions. Key to photoreceptor function is the ability to transmit the signal that they generate in response to light to other neurons in the retina for processing of visual signals and their communication to the brain. For this to occur, photoreceptors form elaborate synapses with the downstream neurons, the bipolar cells (BC). Deficits in synaptic communication between photoreceptors and bipolar cells are known to cause congenital stationary blindness in humans, various forms of rod/cone dystrophies and frequent co-morbidity with many other ocular conditions. The long term goal of our collaborative program is to obtain atomic level view of molecular organization of machinery that enable synaptic communication of the photoreceptors with the hope to better understand blinding conditions and devising strategies for their treatment. Recent research from our laboratories and others have identified several molecules critical for the synaptic communication of photoreceptors. We have further discovered that many of these components are scaffolded into macromolecular assemblies that span the synaptic cleft and physically integrate pre-synaptic elements of photoreceptors with post-synaptic receptors in BC. Specifically, we found that the postsynaptic receptor on BC: mGluR6 interacts with two cell-adhesion molecules in photoreceptors: ELFN1 and ELFN2. Furthermore, the machinery that drives excitation of BC in response to synaptic photoreceptor inputs is associated with an orphan receptor GPR179 which in turn is integrated with pre-synaptic cell adhesion-like molecule pikachurin (Pika) in photoreceptors. We also documented that loss of this organization abolishes synaptic transmission leading to night blindness. However, at the moment we know absolutely nothing about structural basis of these trans-synaptic complexes. Proposed studies aim to fill this gap by determining the atomic structures of the key trans-synaptic scaffolds: ELFN1-mGluR6 and Pika-GPR179 complexes and probing their biochemical mechanisms. This will be achieved by highly synergistic international collaboration leveraging expertise in biochemistry and cell biology of photoreceptor synaptic proteins and recent advances in high resolution cryogenic electron microscopy (CryoEM) to obtain high resolution molecular structures of the complexes probing their mechanisms at exceedingly precise level. The premise of this proposal is that understanding synaptic organization of photoreceptors would lead to novel therapeutic strategies for ameliorating blindness.

项目摘要 对于我们的视力，杆和锥形感受器是必不可少的。他们的死亡或功能障碍是基础 导致绝大多数盲视网膜条件。光感受器函数的关键是传输的能力 信号表明，它们会响应视网膜中其他神经元的光来处理视觉信号和 他们与大脑的交流。为此，光感受器与 下游神经元，双极细胞（BC）。光感受器和 已知双极细胞在人类中引起先天性固定失明，各种形式的棒/锥体 在许多其他眼部条件下，营养不良和频繁的合并症。我们合作的长期目标 程序是为了获得启用突触的机械分子组织的原子级别视图 希望能够更好地了解盲目条件并设计的光感受器的通信 他们的治疗策略。 我们的实验室和其他人的最新研究确定了几个对人物至关重要的分子 光感受器的突触通信。我们进一步发现，其中许多组件是 脚手架成跨突触裂缝并物理整合突触的大分子组件 卑诗省具有后突触受体的光感受器的元素。具体来说，我们发现突触后的 BC上的受体：MGLUR6与感光体中的两个细胞粘附分子相互作用：ELFN1和ELFN2。 此外，响应突触光感受器输入而驱动BC激发的机械是 与孤儿受体GPR179相关，该孤儿受体与突触前细胞粘附一样集成 光感受器中的分子pikachurin（Pika）。我们还记录了失去该组织的废除 突触传播导致夜失明。但是，目前我们对 这些反射突触复合物的结构基础。 拟议的研究旨在通过确定关键反式突触的原子结构来填补这一空白 脚手架：ELFN1-MGLUR6和PIKA-GPR179复合物，并探测其生化机制。这会 可以通过高度协同的国际合作来实现生物化学和细胞生物学专业知识 光感受器突触蛋白以及高分辨率低温电子显微镜的最新进展 （冷冻）获得探测其机制的配合物的高分辨率分子结构 非常精确的水平。该提议的前提是了解 感光细胞将导致新型的治疗策略，以改善失明。