内体 G 蛋白偶联受体的治疗靶向。
Therapeutic Targeting of Endosomal G-Protein-Coupled Receptors.
机构信息
Departments of Surgery and Pharmacology, Columbia University College of Physicians and Surgeons, Columbia University in the City of New York, 21 Audubon Avenue, Room 209, New York City, NY 10032, USA.
Gastroenterology Drug Discovery Unit (GI DDU), Takeda Pharmaceuticals U.S.A. Inc., 35 Landsdowne Street, Cambridge, MA 02139, USA.
出版信息
Trends Pharmacol Sci. 2018 Oct;39(10):879-891. doi: 10.1016/j.tips.2018.08.003. Epub 2018 Sep 1.
G-protein-coupled receptors (GPCRs) are conventionally considered to function at the plasma membrane, where they detect extracellular ligands and activate heterotrimeric G proteins that transmit intracellular signals. Consequently, drug discovery efforts have focused on identification of agonists and antagonists of cell surface GPCRs. However, β-arrestin (ARR)-dependent desensitization and endocytosis rapidly terminate G protein signaling at the plasma membrane. Emerging evidence indicates that GPCRs can continue to signal from endosomes by G-protein- and βARR-dependent processes. By regulating the duration and location of intracellular signaling events, GPCRs in endosomes control critically important processes, including gene transcription and ion channel activity. Thus, GPCRs in endosomes, in addition to at the cell surface, have emerged as important therapeutic targets.
G 蛋白偶联受体（GPCRs）通常被认为在质膜上发挥作用，在质膜上，它们可以检测细胞外配体并激活异三聚体 G 蛋白，从而传递细胞内信号。因此，药物发现工作的重点一直放在鉴定细胞表面 GPCRs 的激动剂和拮抗剂上。然而，β-arrestin（ARR）依赖性脱敏和内吞作用会迅速终止质膜上的 G 蛋白信号。新出现的证据表明，GPCR 可以通过 G 蛋白和βARR 依赖性过程继续从内体发出信号。通过调节细胞内信号事件的持续时间和位置，内体中的 GPCR 控制着包括基因转录和离子通道活性在内的重要过程。因此，除了在细胞表面，内体中的 GPCR 已成为重要的治疗靶点。
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