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Activity-Based Sensing with a Metal-Directed Acyl Imidazole Strategy Reveals Cell Type-Dependent Pools of Labile Brain Copper
Journal of the American Chemical Society ( IF 14.4 ) Pub Date : 2020-08-20 , DOI: 10.1021/jacs.0c05727 Sumin Lee , Clive Yik-Sham Chung , Pei Liu , Laura Craciun , Yuki Nishikawa 1, 2 , Kevin J Bruemmer , Itaru Hamachi 1, 2 , Kaoru Saijo , Evan W Miller , Christopher J Chang
Journal of the American Chemical Society ( IF 14.4 ) Pub Date : 2020-08-20 , DOI: 10.1021/jacs.0c05727 Sumin Lee , Clive Yik-Sham Chung , Pei Liu , Laura Craciun , Yuki Nishikawa 1, 2 , Kevin J Bruemmer , Itaru Hamachi 1, 2 , Kaoru Saijo , Evan W Miller , Christopher J Chang
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Copper is a required nutrient for life and particularly important to the brain and central nervous system. Indeed, copper redox activity is essential to maintaining normal physiological responses spanning neural signaling to metabolism, but at the same time copper misregulation is associated with inflammation and neurodegeneration. As such, chemical probes that can track dynamic changes in copper with spatial resolution, especially in loosely bound, labile forms, are valuable tools to identify and characterize its contributions to healthy and disease states. In this report, we present an activity-based sensing (ABS) strategy for copper detection in live cells that preserves spatial information by a copper-dependent bioconjugation reaction. Specifically, we designed copper-directed acyl imidazole dyes that operate through copper-mediated activation of acyl imidazole electrophiles for subsequent labeling of proximal proteins at sites of elevated labile copper to provide a permanent stain that resists washing and fixation. To showcase the utility of this new ABS platform, we sought to characterize labile copper pools in the three main cell types in the brain: neurons, astrocytes, and microglia. Exposure of each of these cell types to physiologically relevant stimuli shows distinct changes in labile copper pools. Neurons display translocation of labile copper from somatic cell bodies to peripheral processes upon activation, whereas astrocytes and microglia exhibit global decreases and increases in intracellular labile copper pools, respectively, after exposure to inflammatory stimuli. This work provides foundational information on cell type-dependent homeostasis of copper, an essential metal in the brain, as well as a starting point for the design of new activity-based probes for metals and other dynamic signaling and stress analytes in biology.
中文翻译：
基于活动的传感与金属定向酰基咪唑策略揭示了不稳定脑铜的细胞类型依赖性池
铜是生命所需的营养素，对大脑和中枢神经系统尤其重要。事实上，铜的氧化还原活性对于维持从神经信号传导到新陈代谢的正常生理反应至关重要，但同时铜的失调与炎症和神经退行性疾病有关。因此，能够以空间分辨率追踪铜动态变化的化学探针，尤其是松散结合、不稳定形式的铜，是识别和表征其对健康和疾病状态的贡献的宝贵工具。在本报告中，我们提出了一种用于活细胞中铜检测的基于活动的传感（ABS）策略，该策略通过铜依赖性生物共轭反应保留空间信息。具体来说，我们设计了铜导向的酰基咪唑染料，该染料通过铜介导的酰基咪唑亲电子试剂的活化来进行操作，随后在不稳定铜升高的位点标记近端蛋白质，从而提供耐洗涤和固定的永久染色。为了展示这个新 ABS 平台的实用性，我们试图表征大脑中三种主要细胞类型（神经元、星形胶质细胞和小胶质细胞）中不稳定铜池的特征。这些细胞类型中的每一种暴露于生理相关的刺激都显示出不稳定铜池的明显变化。神经元在激活时表现出不稳定铜从体细胞体易位到外周过程，而星形胶质细胞和小胶质细胞在暴露于炎症刺激后分别表现出细胞内不稳定铜池的整体减少和增加。 这项工作提供了关于铜（大脑中必需金属）的细胞类型依赖性稳态的基础信息，以及设计用于金属和生物学中其他动态信号和应激分析物的新的基于活性的探针的起点。
更新日期：2020-08-20
中文翻译：
基于活动的传感与金属定向酰基咪唑策略揭示了不稳定脑铜的细胞类型依赖性池
铜是生命所需的营养素，对大脑和中枢神经系统尤其重要。事实上，铜的氧化还原活性对于维持从神经信号传导到新陈代谢的正常生理反应至关重要，但同时铜的失调与炎症和神经退行性疾病有关。因此，能够以空间分辨率追踪铜动态变化的化学探针，尤其是松散结合、不稳定形式的铜，是识别和表征其对健康和疾病状态的贡献的宝贵工具。在本报告中，我们提出了一种用于活细胞中铜检测的基于活动的传感（ABS）策略，该策略通过铜依赖性生物共轭反应保留空间信息。具体来说，我们设计了铜导向的酰基咪唑染料，该染料通过铜介导的酰基咪唑亲电子试剂的活化来进行操作，随后在不稳定铜升高的位点标记近端蛋白质，从而提供耐洗涤和固定的永久染色。为了展示这个新 ABS 平台的实用性，我们试图表征大脑中三种主要细胞类型（神经元、星形胶质细胞和小胶质细胞）中不稳定铜池的特征。这些细胞类型中的每一种暴露于生理相关的刺激都显示出不稳定铜池的明显变化。神经元在激活时表现出不稳定铜从体细胞体易位到外周过程，而星形胶质细胞和小胶质细胞在暴露于炎症刺激后分别表现出细胞内不稳定铜池的整体减少和增加。 这项工作提供了关于铜（大脑中必需金属）的细胞类型依赖性稳态的基础信息，以及设计用于金属和生物学中其他动态信号和应激分析物的新的基于活性的探针的起点。
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