Regulation of Photoreceptor Neurotransmission

感光神经传递的调节

• 批准号: 8755176
• 负责人: WALLACE B THORESON
• 金额: $ 38.9万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-06-01 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8755176
• 关键词: Acceleration; Biophysical Process; Ca(2+)-Calmodulin Dependent Protein Kinase; Calcium; Calcium Channel; Calcium ion; Calmodulin; Cells; Computer Simulation; Cone; Confocal Microscopy; Darkness; Dependence; Diffuse; Diffusion; Disease; Docking; Electric Capacitance; Electrophysiology (science); Endocytosis; Endocytosis Inhibition; Endoplasmic Reticulum; Event; Eye; Glutamates; Heterogeneity; Image; Individual; Ions; Ischemia; Label; Light; Link; Location; Macular degeneration; Measurement; Measures; Mediating; Membrane; Membrane Potentials; Microscopy; Modeling; Molecular; Mutation; Neuromodulator; Perikaryon; Photoreceptors; Presynaptic Terminals; Process; Prosthesis; Proteins; Regulation; Retina; Retinal; Shapes; Signal Transduction; Site; Speed; Synapses; Synaptic Vesicles; Techniques; Testing; Therapeutic Intervention; Time; Vertebrate Photoreceptors; Vesicle; Vision; Whole-Cell Recordings; base; design; extracellular; functional status; neuronal cell body; neurotransmission; optogenetics; particle; public health relevance; research study; response; retinal progenitor cell; retinal rods; ribbon synapse; spatial relationship; therapy design; voltage

DESCRIPTION (provided by applicant): Light responses of photoreceptors are transmitted across the first synapse in the retina by changes in the ongoing release of glutamate-filled vesicles. Aim 1 proposes to identify the mechanisms that limit rates of ongoing release from cones in light and dark. The rate-limiting steps in continuous release are calcium-dependent, thus linking light-evoked changes in membrane potential to release rates through voltage-dependent changes in calcium entry. Modeling, imaging, and electrophysiology will be used to test the hypothesis that the actions of calmodulin and calmodulin kinase II regulate sustained release by speeding molecular priming of synaptic vesicles or by enhancing vesicle attachment at the ribbon-style active zone. Experiments also test whether the rate of sustained release may be limited by the rate at which the functional status of release sites can be restored after a prio vesicle fusion event. One way in which prior release might restrict subsequent release site function is by disrupting the close spatial relationship between calcium channels and release sites. Unlike cones where release occurs only at ribbon-style active zones, most of the slow sustained release from rods occurs at ectopic sites outside the active zone. This ectopic, non-ribbon release is driven by release of calcium stored in the endoplasmic reticulum. Aim 2 tests the hypothesis that sustained release of calcium from the endoplasmic reticulum drives synaptic release from rods in darkness and that this release from intracellular stores is sustained by the continuous tunneling of calcium ions through endoplasmic reticulum from perikaryon to synaptic terminal. Cones have as many as 50 ribbon-style active zones apiece. Aim 3 asks whether calcium changes at individual ribbons in a cone differ in their voltage-dependence, thus promoting synaptic heterogeneity, or whether they operate like a single distributed ribbon. Together, these experiments are designed to identify key processes that shape vision at the first synapse in the retina and are essential for understanding the consequences of disease-related changes in synaptic activity as well as for restoring normal visual function by therapeutic interventions.

描述（由申请人提供）：光感受器的光反应通过充满谷氨酸的囊泡持续释放的变化传递到视网膜中的第一个突触。目的1提出了确定机制，限制正在进行的释放率从锥在光明和黑暗。在连续释放的限速步骤是钙依赖性的，从而通过钙离子进入的电压依赖性变化将光诱发的膜电位变化与释放速率联系起来。建模，成像和电生理学将被用来测试的假设，钙调蛋白和钙调蛋白激酶II的行动调节持续释放，通过加速分子引发的突触囊泡或通过增强囊泡附着在带状风格的活动区。实验还测试了持续释放的速率是否可能受到释放位点的功能状态在先前囊泡融合事件后可以恢复的速率的限制。先前的释放可能限制随后的释放位点功能的一种方式是通过破坏钙通道和释放位点之间的紧密空间关系。与仅在带状活性区释放的视锥不同，大多数从视杆的缓慢持续释放发生在活性区外的异位部位。这种异位的非带状释放是由储存在内质网中的钙释放驱动的。目的2测试的假设，持续释放的钙从内质网驱动突触释放杆在黑暗中，这种释放从细胞内存储是持续的钙离子隧道通过内质网从核周到突触末端。每个锥体有多达50个带状活动区。目的3询问是否钙的变化在个别丝带在一个锥不同的电压依赖性，从而促进突触的异质性，或者他们是否像一个单一的分布式丝带。总之，这些实验旨在确定在视网膜中的第一个突触处形成视觉的关键过程，并且对于理解突触活动中疾病相关变化的后果以及通过治疗干预恢复正常视觉功能至关重要。