Investigating individual G-protein-coupled receptors (GPCRs) involved in various signaling cascades can unlock a myriad of invaluable physiological findings. One of the promising strategies for addressing the activity of each subtype of receptor is to design chemical turn-on switches on the target receptors. However, valid methods to selectively control class A GPCRs, the largest receptor family encoded in the human genome, remain limited. Here, we describe a novel approach to chemogenetically manipulate activity of engineered class A GPCRs carrying a His₄ tag, using metal complex–agonist conjugates (MACs). This manipulation is termed coordination tethering. With the assistance of coordination bonds, MACs showed 10–100-fold lower EC₅₀ values in the engineered receptors, compared with wild-type receptors. Such coordination tethering enabled selective activation of β₂-adrenoceptors and muscarinic acetylcholine receptors, without loss of natural receptor responses, in living mammalian cells, including primary cultured astrocytes. Our generalized, modular chemogenetic approach should facilitate more precise control and deeper understanding of individual GPCR signaling pathways in living systems.

中文翻译：

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使用Ni（II）配合物-激动剂共轭物的化学生成方法允许A类G蛋白偶联受体的选择性激活。

研究涉及各种信号级联反应的单个G蛋白偶联受体（GPCR）可以解开无数宝贵的生理发现。解决受体每种亚型活性的一种有前途的策略是在靶受体上设计化学开启开关。但是，有效控制选择性控制A类GPCR（人类基因组中编码的最大受体家族）的有效方法仍然有限。在这里，我们描述了一种使用金属络合物-激动剂偶联物（MACs）化学上操纵带有His ₄标签的工程A类GPCR活性的新方法。这种操作称为协调网络共享。在协调债券的协助下，MAC的EC ₅₀降低了10-100倍与野生型受体相比，改造后的受体具有更高的值。这种协调启用束缚的β选择性激活₂肾上腺素能受体和毒蕈碱乙酰胆碱受体，没有天然受体反应损失，在活的哺乳动物细胞，包括原代培养的星形胶质细胞。我们通用的模块化化学发生方法应有助于更精确地控制和更深入地了解生命系统中各个GPCR信号通路。