Structural landscape of photoreceptor synapses

感光器突触的结构景观

• 批准号: 10522890
• 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/10522890
• 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; Disease; Electron Microscopy; Elements; Functional disorder; G-Protein-Coupled Receptors; GTP-Binding Protein Regulators; Glean; Glutamates; Goals; Human; India; International; Laboratories; Lead; 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; Retinitis Pigmentosa; Rod; Role; Sensory; Signal Transduction; Site-Directed Mutagenesis; Structure; Synapses; Synaptic Cleft; Synaptic Receptors; Synaptic Transmission; System; Vision; Work; comorbidity; cryogenics; experimental study; extracellular; follow-up; improved; interdisciplinary approach; macromolecular assembly; novel therapeutic intervention; postsynaptic; programs; protein protein interaction; receptor; reconstitution; response; retinal rods; scaffold; success; synaptic function; therapy development; 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.

项目概要 视杆细胞和视锥细胞感光器对于我们的视觉是不可或缺的。他们的死亡或功能障碍是潜在的 导致绝大多数视网膜失明的原因。光感受器功能的关键是传输光线的能力 它们响应光而向视网膜中的其他神经元发出信号，以处理视觉信号和 他们与大脑的沟通。为了实现这一点，光感受器与光感受器形成复杂的突触。 下游神经元，双极细胞（BC）。光感受器和光感受器之间的突触通讯缺陷 已知双极细胞会导致人类先天性静止性失明，各种形式的视杆细胞/视锥细胞 营养不良以及与许多其他眼部疾病的频繁共病。我们合作的长期目标 程序是获得使突触能够发生的机器分子组织的原子水平视图 光感受器之间的交流，希望更好地了解致盲条件并进行设计 他们的治疗策略。 我们的实验室和其他实验室的最新研究已经确定了几种对 光感受器的突触通讯。我们进一步发现，其中许多组件是 支架形成跨越突触间隙并物理整合突触前的大分子组件 BC 中具有突触后受体的光感受器元件。具体来说，我们发现突触后 BC 上的受体：mGluR6 与光感受器中的两个细胞粘附分子 ELFN1 和 ELFN2 相互作用。 此外，响应突触感光器输入而驱动 BC 兴奋的机制是 与孤儿受体 GPR179 相关，而孤儿受体 GPR179 又与突触前细胞粘附样整合 光感受器中的皮卡丘林 (Pika) 分子。我们还记录了该组织的丧失废除了 突触传递导致夜盲症。然而，目前我们对此一无所知 这些跨突触复合体的结构基础。 拟议的研究旨在通过确定关键跨突触的原子结构来填补这一空白 支架：ELFN1-mGluR6 和 Pika-GPR179 复合物并探讨其生化机制。这将 通过利用生物化学和细胞生物学专业知识的高度协同国际合作来实现 光感受器突触蛋白的研究和高分辨率低温电子显微镜的最新进展 (CryoEM) 获得复合物的高分辨率分子结构，探索其机制 极其精确的水平。该提案的前提是理解突触组织 光感受器将带来改善失明的新治疗策略。