Department of Psychiatry, University of California, San Francisco, San Francisco, CA 94143, USA.
Structural Biology Brussels, Vrije Universiteit Brussel, 1050 Brussels, Belgium.
Neuron. 2018 Jun 6;98(5):963-976.e5. doi: 10.1016/j.neuron.2018.04.021. Epub 2018 May 10.
Opioid receptors (ORs) precisely modulate behavior when activated by native peptide ligands but distort behaviors to produce pathology when activated by non-peptide drugs. A fundamental question is how drugs differ from peptides in their actions on target neurons. Here, we show that drugs differ in the subcellular location at which they activate ORs. We develop a genetically encoded biosensor that directly detects ligand-induced activation of ORs and uncover a real-time map of the spatiotemporal organization of OR activation in living neurons. Peptide agonists produce a characteristic activation pattern initiated in the plasma membrane and propagating to endosomes after receptor internalization. Drugs produce a different activation pattern by additionally driving OR activation in the somatic Golgi apparatus and Golgi elements extending throughout the dendritic arbor. These results establish an approach to probe the cellular basis of neuromodulation and reveal that drugs distort the spatiotemporal landscape of neuronal OR activation.
阿片受体（OR）在被天然肽配体激活时能精确调节行为，但在被非肽类药物激活时会扭曲行为，导致病理状态。一个基本问题是，药物与肽类在作用于靶神经元时有何不同。在这里，我们表明，药物在激活 OR 的亚细胞位置上存在差异。我们开发了一种遗传编码的生物传感器，可直接检测配体诱导的 OR 激活，并揭示了活神经元中 OR 激活的时空组织的实时图谱。肽激动剂产生一种特征性的激活模式，该模式从质膜开始，在受体内化后传播到内体。药物通过另外在体细胞高尔基体和延伸到整个树突状分支的高尔基体元件中驱动 OR 激活，产生不同的激活模式。这些结果建立了一种探测神经调节细胞基础的方法，并揭示了药物会扭曲神经元 OR 激活的时空景观。
