Molecular mechanisms of retinal ON-bipolar cell signaling

视网膜ON-双极细胞信号传导的分子机制

• 批准号: 10596061
• 负责人: ROBERT M DUVOISIN
• 金额: $ 52.14万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10596061
• 关键词: Affect; Afferent Neurons; Amacrine Cells; Cations; Cell physiology; Cells; Coupled; Dark Adaptation; Darkness; Data; Dendrites; Detection; Diglycerides; Disease; Drug Targeting; Electrophysiology (science); Electroretinography; Exposure to; Foundations; Frequencies; G-Protein Signaling Pathway; G-Protein-Coupled Receptors; GRM5 gene; GRM6 gene; Genes; Genetic; Glutamates; Goals; Health; Image; Knockout Mice; Knowledge; Light; Light Cell; Lighting; Mass Spectrum Analysis; Measures; Mediating; Membrane; Molecular; Mus; Mutation; Neurons; Night Blindness; Output; PRKCA gene; Pathway interactions; Phospholipase C; Phosphorylation; Photons; Photoreceptors; Play; Potassium Channel; Presynaptic Terminals; Process; Production; Property; Proteins; Publishing; Recovery; Regulation; Research; Retina; Retinal Cone; Rod; Role; Signal Pathway; Signal Transduction; Signaling Protein; Site; Stimulus; Synapses; System; TRPM1 gene; Testing; Vertebrate Photoreceptors; Vertebrates; Vision; Visual; Visual System; Visual impairment; Work; cell type; forest; ganglion cell; human model; light intensity; light transmission; mouse model; nervous system disorder; novel; patch clamp; pharmacologic; protein function; receptor; response; retinal neuron; retinal rods; segregation; sensory system; side effect; targeted agent; transmission process; virtual

The retina is exposed to light intensities that vary over nine orders of magnitude, from a cloudy night in a forest to a sunny day on a snowy mountainside, and to images of varying contrast and frequency. To optimize vision over this entire range, the response properties of the retina change as a function of the stimuli at both the cellular and network level, a process termed adaptation. The long-term goal of the proposed research is to explain the molecular basis for regulation of the light response in retinal ON-bipolar cells. These cells mediate the transmission of light responses between photoreceptors and ganglion cells and are key sites of adaptation. Rod bipolar cells receive light-driven synaptic input from rod photoreceptors and drive retinal output via synapses onto AII amacrine cells. While dark-adapted rod bipolar cells can transmit single photon responses in starlight, they are also able to transmit contrast changes in moderate background light. The mechanisms which optimize rod bipolar cell function under different lighting conditions remain unknown. Our recent work suggests that a novel mGlu5-based pathway operating in parallel to the primary light-response pathway may modulate the ON-bipolar cell responses. Further, we have identified a potassium channel, Kv11.1, that appears to regulate dark adaptation, and may be regulated by PKCα, which is abundantly expressed in rod bipolar cells. In the dark, photoreceptors release glutamate onto dendrites of ON-bipolar cells, and decrease glutamate release in response to light stimuli. The light response of ON-bipolar cells is mediated by a unique, sign- inverting pathway initiated by mGlu6, a G protein-coupled receptor in the ON-bipolar cell dendrites. In the dark, tonic activation of the mGlu6 pathway maintains the TRPM1 cation channel in a closed state. In response to light stimuli, mGlu6 is inactivated, allowing TRPM1 channels to open and depolarize the cell. The mGlu6- TRPM1 pathway is conserved in all vertebrates, and mutations in mGlu6 and TRPM1 cause congenital stationary night blindness (CSNB) in humans and mouse models. Despite its central importance in vision, the molecular mechanisms by which the primary excitatory pathway is modulated under different conditions remain unknown. Based on analogy with other systems, and our Preliminary Studies, we hypothesize that mGlu5 receptors, Kv11.1 channels and PKCα modulate the output of the mGlu6-TRPM1 pathway.

视网膜暴露在变化超过九个数量级的光强度下，从多云的夜晚到 森林到白雪皑皑的山坡上阳光明媚的一天，以及不同对比度和频率的图像。优化 在整个范围内的视力中，视网膜的响应特性随着两个方向的刺激而变化 蜂窝和网络级别，这个过程称为适应。拟议研究的长期目标是 解释视网膜ON-双极细胞光反应调节的分子基础。这些 细胞介导感光器和神经节细胞之间光反应的传递，是关键部位 的适应。杆状双极细胞接收来自杆状感光器的光驱动突触输入并驱动视网膜 通过突触输出到所有无长突细胞上。虽然暗适应杆双极细胞可以传输单光子 除了在星光下响应之外，它们还能够在中等背景光下传输对比度变化。这 在不同光照条件下优化杆状双极细胞功能的机制仍然未知。我们的 最近的工作表明，一种基于 mGlu5 的新型途径与初级光反应并行运行 途径可能调节 ON-双极细胞反应。此外，我们还发现了钾通道， Kv11.1，似乎调节暗适应，并且可能受 PKCα 调节，PKCα 丰富 在杆状双极细胞中表达。 在黑暗中，光感受器将谷氨酸释放到 ON-双极细胞的树突上，并减少谷氨酸 响应光刺激而释放。 ON-双极细胞的光响应是由一种独特的信号介导的 由 ON-双极细胞树突中的 G 蛋白偶联受体 mGlu6 启动的反转途径。在黑暗中， mGlu6 途径的强直激活使 TRPM1 阳离子通道保持关闭状态。作为回应 在光刺激下，mGlu6 失活，从而允许 TRPM1 通道打开并使细胞去极化。 mGlu6- TRPM1 通路在所有脊椎动物中都是保守的，mGlu6 和 TRPM1 的突变会导致先天性 人类和小鼠模型中的静止性夜盲症（CSNB）。尽管它对于视觉至关重要， 不同条件下调节初级兴奋途径的分子机制 情况仍未知。基于与其他系统的类比以及我们的初步研究，我们 假设 mGlu5 受体、Kv11.1 通道和 PKCα 调节 mGlu6-TRPM1 的输出 途径。

项目成果

Mice Lacking Gpr179 with Complete Congenital Stationary Night Blindness Are a Good Model for Myopia.

• DOI: 10.3390/ijms24010219
• 发表时间: 2022-12-22
• 期刊: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
• 影响因子: 5.6
• 作者: Wilmet, Baptiste;Callebert, Jacques;Duvoisin, Robert;Goulet, Ruben;Tourain, Christophe;Michiels, Christelle;Frederiksen, Helen;Schaeffel, Frank;Marre, Olivier;Sahel, Jose Alain;Audo, Isabelle;Picaud, Serge;Zeitz, Christina
• 通讯作者: Zeitz, Christina