This article is part of the Advances in GPCR Signal Transduction special issue. Our understanding of the G protein-coupled receptor (GPCR) family of cell surface receptors continues to advance at a pace. Driven by a flow of new atomic level structures and novel insights into receptor signal transduction, we are learning more of the fundamental biology of this therapeutically important class of receptors. In this Special Edition of ACS Pharmacology and Translational Science we have attempted to capture some of these advances in a mixture of articles that includes reviews, original research papers, a perspective, and the outcome of a workshop. Not surprisingly a number of articles have focused on the question of ligand bias or functional selectivity. Understanding the rules that govern the rational-design of GPCR ligands that drive receptor signaling toward pathways that promote clinical efficacy and away from pathways that mediate toxicity/adverse outcomes has been the aim of many of the world’s leading GPCR research groups.(1−5) Here the challenges of the identification and characterization of biased ligands is exemplified in an article by Wouters et al.(6) who focus on the cannabinoid CB1 receptor to discover novel biased ligands. Understanding the mechanism of biased agonism is an area of intense investigation and is covered here in an article by Verweij et al.,(7) where the role played by receptor phosphorylation in driving differential signaling is considered using the histamine H4 receptor as an exemplar. It is now clear that mechanisms other than those centered on receptor phosphorylation(8) and arrestin interaction(9) may underlie biased signaling, a point made clearly in the article by van der Velden et al.,(10) in which ligand binding kinetics is considered not only in the context of functional selectivity but also as an important contributing factor to in vivo efficacy of class A GPCR ligands. van der Velden also touches on the importance of signaling not from the membrane but from endosomal compartments, a topic expanded on in a review article by Plouffe et al.(11) In this contribution Plouffe et al. not only provide an update on the latest advances in our understanding of GPCR signaling from intracellular compartments, but importantly places this process in a physiological and pathophysiological context by focusing on the importance of intracellular compartmental signaling in cardiac function. The Plouffe article is just one of a number of contributions that draws a link between molecular pharmacology and translational science. Prominent among these is an article by Abd-Elrahman et al.(12) in which they present evidence that the Type 5 metabotropic glutamate receptor (mGluR5) contributes to the pathology of Alzheimer’s disease. The translational theme is also taken up by Eiden et al.(13) in a slightly different contribution summarizing the outcome of a workshop that drew together the world’s experts in peptide-liganded receptors asking what are the best receptor classes and strategies to target peptide-liganded receptors in the treatment of neurological and psychiatric disorders? Among the most relevant areas of translational research in the GPCR field is that of the role of GPCRs in inflammation. Here the review article by Dahlgren et al.(14) addresses the role of GPCRs in neutrophil biology and how allosteric modulators and biased ligands targeting neutrophil GPCRs might offer novel therapeutic approaches to the control of inflammation. Where would a special edition focused on GPCRs be without an article on atomic structure? In a contribution from Liang et al.,(15) cryo-electron microscopy structures provide an atomic level understanding of ligand specificity of the calcitonin receptor-like receptor (CLR). This receptor, when dimerized with its chaperon protein RAMP-1, generates the calcitonin gene-related peptide receptor (CGRP), whereas dimerization with RAMP2 and RAMP3 results in the adrenomedullin receptors 1 and 2, respectively. The paper by Liang et al. provides a mechanistic explanation for the allosteric modulation of CLR by the RAMP-family. Staying with this class B receptor family Garelja et al.(16) investigate the mechanism of differential signaling of CLR when dimerized with RAMP1, 2, and 3. Advances in our understanding of CLR:RAMP dimers is further extended by Gingell et al.(17) who describe how CLR dimerization with different RAMP proteins promotes different mechanisms of receptor internalization, while Hay et al.(18) present evidence for small drug-like modulators of CLR:RAMP combinations. Discussion of Class B receptors is not however restricted to CLR-based receptors with a contribution from Fang et al.(19) who provide mechanistic insight into the internalization of the glucagon-like peptide-1 receptor. Finally, our Special Edition presents a series of articles demonstrating the importance of novel post-translational modifications. Goth et al.(20) review the area of post-translational modification of extracellular domains on GPCRs. This includes the importance of glycosylation, tyrosine sulfation, modification of proteolytic cleavage sites, and extracellular sites of phosphorylation. The importance of extracellular post-translational modifications is expanded on further in the contribution by Marullo et al.(21) in which they review the role of N-glycan chains located at the N-terminus of GPCRs that act as mechano-sensors playing a role in cell:cell interactions that can provide a means of mechanical activation of GPCRs. This Special Edition has drawn a number of contributions from the newly established European network of scientists drawn together under the banner of the European Network on Signal Transduction (ERNEST). This exciting collaborative network brings together scientists from within the European Union and also associated countries to tackle unresolved questions in GPCR signal transduction and biology. The aims, objectives, and work packages of ERNEST are presented in an article by Sommer et al.(22) Overall, we hope that you find this special edition both informative and enjoyable. Views expressed in this editorial are those of the authors and not necessarily the views of the ACS. This article references 22 other publications.

中文翻译：

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G蛋白偶联受体信号转导进展的社论。

本文是 GPCR信号转导研究进展特刊。我们对细胞表面受体的G蛋白偶联受体（GPCR）家族的了解仍在不断发展。在新的原子级结构和对受体信号转导的新见解的推动下，我们正在学习这种具有治疗重要性的受体的基本生物学知识。在此ACS药理学和转化科学特刊中我们试图通过一系列文章（包括评论，原始研究论文，观点和研讨会的成果）来捕捉其中的一些进步。毫不奇怪，许多文章集中于配体偏倚或功能选择性的问题。理解控制GPCR配体合理设计的规则，这些规则将受体信号转导至可促进临床疗效的途径，并远离介导毒性/不良结果的途径，这已成为许多世界领先的GPCR研究小组的目标（1-5）。Wouters等人在一篇文章中举例说明了鉴定和表征有偏配体的挑战。（6）研究大麻素CB1受体的人发现了新的偏向配体。了解偏向激动的机制是一个需要深入研究的领域，Verweij等人在本文中对此进行了介绍。（7），其中使用组胺H4受体作为范例来考虑受体磷酸化在驱动差异信号中所起的作用。现在清楚的是，除了那些集中于受体磷酸化（8）和抑制蛋白相互作用（9）的机制以外，其他机制可能是有偏向的信号传导的基础，van der Velden等人在文章中明确指出了这一点。，（10），其中配体结合动力学不仅在功能选择性的背景下被考虑，而且是体内重要的促成因素。A类GPCR配体的功效。van der Velden还谈到了不是从膜而是从内体区室发出信号的重要性，Plouffe等人在一篇综述文章中扩展了这个话题。（11）在这一贡献中，Plouffe等人。不仅提供了我们对细胞内区室GPCR信号的了解的最新进展的最新信息，而且还通过关注细胞内区室信号在心脏功能中的重要性，将这一过程置于生理和病理生理环境中。Plouffe的文章只是在分子药理学与转化科学之间建立联系的众多贡献之一。其中最著名的是Abd-Elrahman等人的文章。（12）他们提供了5型代谢型谷氨酸受体（mGluR5）有助于阿尔茨海默氏病病理的证据。Eiden等人也探讨了翻译主题。（13）在一个略有不同的贡献中，总结了一个研讨会的结果，该研讨会召集了世界各地的肽配体受体专家，他们询问在治疗神经病和精神疾病时最佳的受体类别和靶向肽配体受体的最佳策略是什么？GPCR领域中翻译研究的最相关领域包括GPCR在炎症中的作用。这里是Dahlgren等人的评论文章。（14）讨论了GPCR在嗜中性粒细胞生物学中的作用，以及针对嗜中性粒细胞GPCR的变构调节剂和偏配体如何为控制炎症提供新颖的治疗方法。如果没有关于原子结构的文章，那么专门针对GPCR的特别版在哪里呢？在梁等人的贡献。，（15）低温电子显微镜结构提供了对降钙素受体样受体（CLR）的配体特异性的原子水平的理解。当该受体与其伴侣蛋白RAMP-1二聚时，产生降钙素基因相关肽受体（CGRP），而与RAMP2和RAMP3二聚分别产生肾上腺髓质素受体1和2。Liang等人的论文。为RAMP家族对CLR的变构调节提供了机理的解释。住在这个B类受体家族Garelja等。（16）研究了在用RAMP1、2和3二聚化时CLR差异信号的机制。Gingell等人进一步扩展了我们对CLR：RAMP二聚体的理解。（17）描述了用不同的RAMP蛋白进行CLR二聚化如何促进受体内在化的不同机制，而Hay等人（18）提供了CLR：RAMP组合的小型药物样调节剂的证据。但是，Bang受体的讨论并不局限于基于CLR的受体，Fang等人的贡献。（19）他们提供了有关胰高血糖素样肽1受体内在化的机制的见解。最后，我们的特别版提供了一系列文章，证明了新颖的翻译后修饰的重要性。哥特等。（20）综述了GPCR上胞外域的翻译后修饰区域。这包括糖基化，酪氨酸硫酸化，蛋白水解切割位点的修饰和磷酸化的细胞外位点的重要性。Marullo等人的贡献进一步扩展了细胞外翻译后修饰的重要性。（21），他们审查了位于GPCRs N末端的N-聚糖链的作用，该N-聚糖链充当在细胞：细胞相互作用中起作用的机械传感器，可以提供GPCRs的机械激活方式。本特别版在欧洲信号传输网络（ERNEST）的旗帜下，新成立的欧洲科学家网络汇集了许多贡献。这个令人兴奋的合作网络将来自欧盟内部以及相关国家的科学家聚集在一起，共同解决GPCR信号转导和生物学领域尚未解决的问题。Sommer等人在一篇文章中介绍了ERNEST的目的，目标和工作包。（22）总体而言，我们希望您能从此特别版中获得丰富而有趣的信息。本社论中表达的观点只是作者的观点，不一定是ACS的观点。本文引用了其他22个出版物。