利用可光切换的远程拴链配体对多巴胺D1受体的可逆拮抗作用。

IF 3.8 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

ACS Chemical Biology Pub Date : 2025-10-16 DOI:10.1021/acschembio.5c00441

Belinda E Hetzler, Prashant Donthamsetti, Robert M Wolesensky, Cherise Stanley, Ehud Y Isacoff, Dirk Trauner

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引用次数: 0

摘要

多巴胺D1受体（D1R）在健康和疾病中起着关键作用。D1R在整个大脑和身体中广泛表达，并在内源性多巴胺的作用下被动态激活，因此很难以足够的精度靶向该受体。我们之前开发了一种强大的光激活，系固的D1R激动剂，其中一种暂时精确的光开关（P化合物）与特定大脑位置和细胞类型的遗传编码膜锚定蛋白（M蛋白）结合。在这里，我们通过开发一种互补拮抗剂P化合物扩展了我们的方法，该化合物可用于精确定时阻断大脑中D1R的特定种群。我们共同创建了一个强大的工具包，以前所未有的精度询问大脑中的D1R功能。

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Reversible Antagonism of Dopamine D1 Receptor Using a Photoswitchable Remotely Tethered Ligand.

Dopamine D1 receptor (D1R) plays key roles in health and disease. D1R is broadly expressed throughout the brain and body and is dynamically activated in response to endogenous dopamine, making it difficult to target this receptor with sufficient precision. We previously developed a robust light-activatable, tetherable agonist for D1R, wherein a temporally precise photoswitch (the P compound) binds to a genetically encoded membrane anchoring protein (the M protein) in specific brain locations and cell types. Here we extended our approach by developing a complementary antagonist P compound that could be used to block specific populations of D1R in the brain with precise timing. Together, we have generated a robust toolkit for interrogating D1R function in the brain with unprecedented precision.

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来源期刊

ACS Chemical Biology 生物-生化与分子生物学

CiteScore

7.50

自引率

5.00%

发文量

353

审稿时长

3.3 months

期刊介绍： ACS Chemical Biology provides an international forum for the rapid communication of research that broadly embraces the interface between chemistry and biology. The journal also serves as a forum to facilitate the communication between biologists and chemists that will translate into new research opportunities and discoveries. Results will be published in which molecular reasoning has been used to probe questions through in vitro investigations, cell biological methods, or organismic studies. We welcome mechanistic studies on proteins, nucleic acids, sugars, lipids, and nonbiological polymers. The journal serves a large scientific community, exploring cellular function from both chemical and biological perspectives. It is understood that submitted work is based upon original results and has not been published previously.