Calcium channels in retinal photoreceptors

视网膜感光细胞中的钙通道

• 批准号: 10706974
• 负责人: AMY LEE
• 金额: $ 47.65万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10706974
• 关键词: Affect; Animal Model; Architecture; Binding; Blindness; C-terminal; Calcium Channel; Calmodulin; Cell Adhesion Molecules; Cell Transplantation; Clinical; Communication; Compensation; Cone; Data; Development; Disease; Electrophysiology (science); Genes; Glutamates; Goals; Human; Image; In Vitro; Injury; Ions; Knock-in Mouse; Knowledge; Lighting; Mediating; Molecular; Mouse Strains; Mus; Mutant Strains Mice; Mutation; Neurites; Neurophysiology - biologic function; Night Blindness; Pathologic; Pathway interactions; Photoreceptors; Point Mutation; Positioning Attribute; Process; Property; Proteins; RNA Splicing; Recombinants; Research; Resistance; Retina; Retinal Cone; Retinal Diseases; Retinal Photoreceptors; Rod; Role; Shapes; Signal Pathway; Signal Transduction; Source; Structure; Synapses; Synaptic plasticity; Techniques; Testing; Transfection; Variant; Vertebrate Photoreceptors; Vision; Visual impairment; Work; biophysical properties; in vivo; inducible gene expression; innovation; insight; molecular assembly/self assembly; mutant; novel strategies; postsynaptic; presynaptic; ribbon synapse; scaffold; sensor; sight restoration; synaptic function; synaptogenesis; transmission process; transplantation therapy; voltage

The long-term goal of our research is to understand how the properties of Cav channels shape their neural functions. The objective of this competing renewal application is to define the Cav1-dependent signaling pathways that shape the development and plasticity of the photoreceptor (PR) synapse. Among the major Cav1 subtypes expressed in the retina, Cav1.4 is uniquely critical for PR synaptogenesis. How Cav1.4 contributes to this process remains a mystery—a major challenge being that available animal models do not distinguish between the roles of Cav1.4 as a source of Ca2+ ions and as a scaffold for synaptogenic proteins. To overcome this hurdle, we generated a knock-in mouse strain expressing a non-conducting mutant form of Cav1.4. While the molecular organization of PR synapses is largely spared in these mice, the maturation of synaptic ribbons and invagination of postsynaptic neurites into PR terminals is disrupted. Our findings raise the intriguing possibility that the clinical variability associated with CSNB2 could arise from heterogeneous impacts of the mutations on the organization, development, and mature function of the PR synapse. Our central hypothesis is that Cav1.4 mediates Ca2+ signaling pathways that promote the maturation of synaptic ribbons and the postsynaptic architecture of PR synapses via mechanisms that are disrupted in CSNB2. We will test this hypothesis with the following Aims: (1) Elucidate the mechanism whereby Cav1.4 Ca2+ signals regulate the maturation and plasticity of synaptic ribbons (2) Define the role of Cav1 Ca2+ signals in enabling the postsynaptic wiring of PR synapses (3) Determine the impact of pathological variants of human Cav1.4 channels on PR synapse structure and function. The overall impact of our research will be knowledge of: (a) the multi-faceted roles of Cav channels at a synapse that is crucial for vision, and (b) how dysregulation specifically of Cav1.4 could lead to heterogeneous forms of vision impairment. More broadly, our research is expected to provide insights into mechanisms that enable the proper synaptic connectivity in the retina—a requirement for the successful restoration of vision through cell transplantation therapies.

我们研究的长期目标是了解骑士通道的性质如何影响他们 神经功能。此竞争续订应用的目的是定义CAV1依赖性 信号通路，以塑造感光器（PR）突触的发育和可塑性。之中 在视网膜中表达的主要CAV1亚型Cav1.4对于PR突触发生至关重要。如何 CAV1.4对这一过程的贡献仍然是一个神秘的事物 - 主要的挑战是可用的动物 模型不能区分Cav1.4作为Ca2+离子来源的角色，也不会区分为脚手架 突触蛋白。为了克服这一障碍，我们产生了一种表达CAV1.4的非导向突变体形式的敲入小鼠应变。虽然公关突触的分子组织在很大程度上幸免于此 这些小鼠，突触丝带的成熟和突触后神经运动的起伏 被破坏了。我们的发现提出了与CSNB2相关的临床变异性的有趣可能性 可能是由于突变对组织，发展和成熟的异构影响而产生的 PR突触的功能。我们的中心假设是CAV1.4介导Ca2+信号传导途径 促进突触丝带的成熟和通过 CSNB2中破坏的机制。我们将以以下目的检验该假设：（1）阐明 CAV1.4 Ca2+信号调节突触丝带的成熟和可塑性的机制（2）定义 Cav1 Ca2+信号在实现PR突触的突触后接线中的作用（3）确定 我们的CAV1.4通道对PR突触结构和功能的总体影响。 研究将了解：（a）在突触中，Cav通道的多面作用，这对于视觉至关重要， （b）CAV1.4的专门调节如何导致视力障碍的异质形式。更多的 从广义上讲，我们的研究有望提供有关能够适当突触的机制的见解 视网膜中的连通性 - 通过细胞移植成功恢复视力的要求 疗法。

项目成果

Transgenic Expression of Cacna1f Rescues Vision and Retinal Morphology in a Mouse Model of Congenital Stationary Night Blindness 2A (CSNB2A).

• DOI: 10.1167/tvst.9.11.19
• 发表时间: 2020-10
• 期刊: Translational vision science & technology
• 影响因子: 3
• 作者: Waldner DM;Ito K;Chen LL;Nguyen L;Chow RL;Lee A;Rancourt DE;Tremblay F;Stell WK;Bech-Hansen NT
• 通讯作者: Bech-Hansen NT

A Comparison of the Primary Sensory Neurons Used in Olfaction and Vision.

• DOI: 10.3389/fncel.2020.595523
• 发表时间: 2020
• 期刊: Frontiers in cellular neuroscience
• 影响因子: 5.3
• 作者: Lankford CK;Laird JG;Inamdar SM;Baker SA
• 通讯作者: Baker SA

Presynaptic calcium channels: specialized control of synaptic neurotransmitter release.

• DOI: 10.1038/s41583-020-0278-2
• 发表时间: 2020-04
• 期刊: Nature reviews. Neuroscience
• 作者: Dolphin AC;Lee A
• 通讯作者: Lee A