Department of Molecular Pharmacology and Therapeutics, Stritch School of Medicine, Loyola University Chicago, 2160 S. 1st Ave., Building 101, Room 2721, Maywood, IL 60153, USA.
Cell Signal. 2013 Mar;25(3):707-16. doi: 10.1016/j.cellsig.2012.11.024. Epub 2012 Nov 29.
G protein-coupled receptors (GPCRs) belong to one of the largest family of signaling receptors in the mammalian genome [1]. GPCRs elicit cellular responses to multiple diverse stimuli and play essential roles in human health and disease. GPCRs have important clinical implications in various diseases and are the targets of approximately 25-50% of all marketed drugs [2,3]. Understanding how GPCRs are regulated is essential to delineating their role in normal physiology and in the pathophysiology of several diseases. Given the vast number and diversity of GPCRs, it is likely that multiple mechanisms exist to regulate GPCR function. While GPCR signaling is typically regulated by desensitization and endocytosis mediated by phosphorylation and β-arrestins, it can also be modulated by ubiquitination. Ubiquitination is emerging an important regulatory process that may have unique roles in governing GPCR trafficking and signaling. Recent studies have revealed a mechanistic link between GPCR phosphorylation, β-arrestins and ubiquitination that may be applicable to some GPCRs but not others. While the function of ubiquitination is generally thought to promote receptor endocytosis and endosomal sorting, recent studies have revealed that ubiquitination also plays an important role in positive regulation of GPCR signaling. Here, we will review recent developments in our understanding of how ubiquitin regulates GPCR endocytic trafficking and how it contributes to signal transduction induced by GPCR activation.
G 蛋白偶联受体（GPCRs）属于哺乳动物基因组中最大的信号受体家族之一[1]。GPCRs 可引发细胞对多种不同刺激的反应，在人类健康和疾病中发挥着重要作用。GPCRs 在各种疾病中有重要的临床意义，是大约 25-50%上市药物的靶点[2,3]。了解 GPCRs 如何被调控对于阐明它们在正常生理和多种疾病病理生理学中的作用至关重要。鉴于 GPCRs 的数量众多且具有多样性，很可能存在多种调节 GPCR 功能的机制。虽然 GPCR 信号通常通过磷酸化和β-arrestin 介导的脱敏和内吞作用来调节，但它也可以通过泛素化来调节。泛素化是一种新兴的重要调控过程，它可能在调节 GPCR 运输和信号转导方面具有独特的作用。最近的研究揭示了 GPCR 磷酸化、β-arrestin 和泛素化之间的一种机制联系，这种联系可能适用于某些 GPCRs，但不适用于其他 GPCRs。虽然泛素化的功能通常被认为是促进受体内吞和内体分选，但最近的研究表明，泛素化在 GPCR 信号的正向调节中也起着重要作用。在这里，我们将回顾我们对泛素如何调节 GPCR 内吞运输以及它如何促进 GPCR 激活诱导的信号转导的理解的最新进展。
