Department of Pharmacology and the Biomedical Sciences Graduate Program, School of Medicine, University of California, San Diego, La Jolla, California.
Department of Pharmacology and the Biomedical Sciences Graduate Program, School of Medicine, University of California, San Diego, La Jolla, California
Pharmacol Rev. 2021 Jan;73(1):120-151. doi: 10.1124/pharmrev.120.000082.
G protein-coupled receptors (GPCRs) are a large family comprising >800 signaling receptors that regulate numerous cellular and physiologic responses. GPCRs have been implicated in numerous diseases and represent the largest class of drug targets. Although advances in GPCR structure and pharmacology have improved drug discovery, the regulation of GPCR function by diverse post-translational modifications (PTMs) has received minimal attention. Over 200 PTMs are known to exist in mammalian cells, yet only a few have been reported for GPCRs. Early studies revealed phosphorylation as a major regulator of GPCR signaling, whereas later reports implicated a function for ubiquitination, glycosylation, and palmitoylation in GPCR biology. Although our knowledge of GPCR phosphorylation is extensive, our knowledge of the modifying enzymes, regulation, and function of other GPCR PTMs is limited. In this review we provide a comprehensive overview of GPCR post-translational modifications with a greater focus on new discoveries. We discuss the subcellular location and regulatory mechanisms that control post-translational modifications of GPCRs. The functional implications of newly discovered GPCR PTMs on receptor folding, biosynthesis, endocytic trafficking, dimerization, compartmentalized signaling, and biased signaling are also provided. Methods to detect and study GPCR PTMs as well as PTM crosstalk are further highlighted. Finally, we conclude with a discussion of the implications of GPCR PTMs in human disease and their importance for drug discovery. SIGNIFICANCE STATEMENT: Post-translational modification of G protein-coupled receptors (GPCRs) controls all aspects of receptor function; however, the detection and study of diverse types of GPCR modifications are limited. A thorough understanding of the role and mechanisms by which diverse post-translational modifications regulate GPCR signaling and trafficking is essential for understanding dysregulated mechanisms in disease and for improving and refining drug development for GPCRs.
G 蛋白偶联受体（GPCRs）是一个包含超过 800 种信号转导受体的大家族，调节着许多细胞和生理反应。GPCRs 与许多疾病有关，是最大的药物靶点类群之一。尽管 GPCR 结构和药理学的进步促进了药物发现，但不同的翻译后修饰（PTMs）对 GPCR 功能的调节却很少受到关注。在哺乳动物细胞中已知存在 200 多种 PTMs，但仅有少数几种被报道存在于 GPCRs 中。早期研究表明磷酸化是 GPCR 信号转导的主要调节因子，而后来的报告则表明泛素化、糖基化和棕榈酰化在 GPCR 生物学中具有功能。虽然我们对 GPCR 磷酸化的了解很广泛，但对其他 GPCR PTM 的修饰酶、调节和功能的了解却很有限。在这篇综述中，我们全面概述了 GPCR 的翻译后修饰，并更加关注新的发现。我们讨论了控制 GPCR 翻译后修饰的亚细胞定位和调节机制。还提供了新发现的 GPCR PTM 对受体折叠、生物合成、内吞运输、二聚化、区室化信号传递和偏向信号传递的功能影响。还进一步强调了检测和研究 GPCR PTM 以及 PTM 串扰的方法。最后，我们讨论了 GPCR PTM 在人类疾病中的意义及其对药物发现的重要性。
意义陈述：G 蛋白偶联受体（GPCRs）的翻译后修饰控制着受体功能的各个方面；然而，对各种 GPCR 修饰的检测和研究却受到限制。深入了解不同的翻译后修饰调节 GPCR 信号转导和运输的作用和机制，对于理解疾病中失调的机制以及改善和优化 GPCR 药物开发至关重要。
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