Article
Biochemistry & Molecular Biology
Ya Zhuo, Joseph M. Crecelius, Adriano Marchese
Summary: This study provides evidence that distal carboxylterminal tail phosphorylation sites specify GRK-arrestin-mediated signaling in CXCR4 and other GPCRs.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2022)
Review
Cell Biology
Haoran Jiang, Daniella Galtes, Jialu Wang, Howard A. Rockman
Summary: This review explores the signaling pathways, dynamic structures, and physiological relevance of the three most important GPCR signaling effectors in the cardiovascular system: heterotrimeric G proteins, GPCR kinases (GRKs), and 8-arrestins. It summarizes their prominent roles in GPCR pharmacology before transitioning into less well-explored areas. The application of new technologies has contributed to an increasing understanding of GPCR structure and downstream effectors.
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY
(2022)
Article
Pharmacology & Pharmacy
Mark von Zastrow
Summary: Advances in proteomic methodologies based on quantitative mass spectrometry are revolutionizing pharmacology and experimental biology. This review focuses on the interplay between G protein-coupled receptor signaling and trafficking in the endocytic network, highlighting recent progress and challenges in elucidating the cellular basis of drug action using proteomic approaches.
MOLECULAR PHARMACOLOGY
(2021)
Review
Cell Biology
Radka Trubacova, Zdenka Drastichova, Jiri Novotny
Summary: This article summarizes the research progress on the signal transduction mediated by thyrotropin-releasing hormone (TRH) receptors and points out future directions for research, aiming to uncover the molecular mechanisms behind TRH receptor-triggered actions and find possible ways to modulate TRH receptor-mediated signaling.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2022)
Article
Multidisciplinary Sciences
Angus Li, Samuel Liu, Rennica Huang, Seungkirl Ahn, Robert J. Lefkowitz
Summary: G protein-coupled receptors (GPCRs) regulate cellular signaling pathways by coupling to G proteins and beta-arrestins. SII, an analog of AngII, activates cellular signaling through beta-arrestin-2-dependent mechanisms but fails to activate G protein. However, overexpression of the receptor can distort the bias of ligands and may not accurately reflect their signaling profile in physiologically relevant contexts.
Article
Biochemistry & Molecular Biology
Masa Mavri, Sanja Glisic, Milan Sencanski, Milka Vrecl, Mette M. Rosenkilde, Katja Spiess, Valentina Kubale
Summary: This study found that all BILF1 receptors undergo dynamin-dependent, clathrin-mediated constitutive endocytosis. In addition, recycling and degradation pathways were proposed for BILF1 receptors after internalization. These findings provide a foundation for further exploration of the translational potential of PLHV BILFs and offer new insights into receptor trafficking.
CELLULAR & MOLECULAR BIOLOGY LETTERS
(2023)
Article
Cell Biology
Jordan T. Bateman, Erica S. Levitt
Summary: G protein-biased opioid agonists are proposed as safer analgesics with less respiratory depression. Studies have linked respiratory depression to G protein bias and intrinsic efficacy, refuting the role of beta-arrestin signaling in opioid-induced respiratory depression.
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY
(2021)
Article
Biochemistry & Molecular Biology
John Janetzko, Ryoji Kise, Benjamin Barsi-Rhyne, Dirk H. Siepe, Franziska M. Heydenreich, Kouki Kawakami, Matthieu Masureel, Shoji Maeda, K. Christopher Garcia, Mark von Zastrow, Asuka Inoue, Brian K. Kobilka
Summary: This study reveals the role of membrane phosphoinositides (PIPs) in β-arrestin recruitment and GPCR-β-arrestin complex dynamics through cell-based and in vitro biophysical assays. GPCRs are classified into two groups, with one requiring PIP binding for β-arrestin recruitment and the other not. Plasma membrane PIPs enhance the active conformation of β-arrestin and stabilize GPCR-β-arrestin complexes by promoting a fully engaged state. As allosteric modulators of GPCR-β-arrestin complex dynamics, membrane PIPs allow for additional conformational diversity beyond GPCR phosphorylation alone. For GPCRs that require membrane PIP binding for β-arrestin recruitment, this provides a mechanism for rapid β-arrestin release upon GPCR translocation to endosomes, enabling its quick recycling.
Article
Multidisciplinary Sciences
Mithu Baidya, Madhu Chaturvedi, Hemlata Dwivedi-Agnihotri, Ashutosh Ranjan, Dominic Devost, Yoon Namkung, Tomasz Maciej Stepniewski, Shubhi Pandey, Minakshi Baruah, Bhanupriya Panigrahi, Parishmita Sarma, Manish K. Yadav, Jagannath Maharana, Ramanuj Banerjee, Kouki Kawakami, Asuka Inoue, Jana Selent, Stephane A. Laporte, Terence E. Hebert, Arun K. Shukla
Summary: This study reveals that synthetic antibodies can be used to modulate GPCR trafficking and signaling in live cells.
NATURE COMMUNICATIONS
(2022)
Article
Multidisciplinary Sciences
Junke Liu, Hengmin Tang, Chanjuan Xu, Shengnan Zhou, Xunying Zhu, Yuanyuan Li, Laurent Prezeau, Tao Xu, Jean-Philippe Pin, Philippe Rondard, Wei Ji, Jianfeng Liu
Summary: This study reveals that the assembly of platelet-activating factor receptor (PAFR) into dimers and oligomers can significantly influence its signaling mode. Oligomerization enhances G protein coupling, while restraining beta-arrestin recruitment and internalization.
NATURE COMMUNICATIONS
(2022)
Review
Biochemistry & Molecular Biology
Sandra Berndt, Ines Liebscher
Summary: SFKs are crucial regulators of cell proliferation, differentiation, and survival, with their expression strongly linked to cancer development and tumor progression. The regulation of SFKs through GPCR-mediated pathways is complex and may involve direct protein interactions or allosteric regulation by arrestins and G proteins. The potential direct interaction between GPCRs and SFKs could lead to a novel mechanism of SFK signaling and identification of new GPCR-SFK interactions.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Multidisciplinary Sciences
Parishmita Sarma, Carlo Marion C. Carino, Deeksha Seetharama, Shubhi Pandey, Hemlata Dwivedi-Agnihotri, Xue Rui, Yubo Cao, Kouki Kawakami, Poonam Kumari, Yu-Chih Chen, Kathryn E. Luker, Prem N. Yadav, Gary D. Luker, Stephane A. Laporte, Xin Chen, Asuka Inoue, Arun K. Shukla
Summary: Chemokine receptors are G protein-coupled receptors (GPCRs) involved in immune responses and characterized by ligand promiscuity. Here, the authors characterize signaling through chemokine receptors CXCR4 and CXCR7, with insights into intrinsic-bias encoded in the CXCR4-CXCR7 system.
NATURE COMMUNICATIONS
(2023)
Article
Multidisciplinary Sciences
Alan Hegron, Chloe J. Peach, Raquel Tonello, Philipp Seemann, Shavonne Teng, Rocco Latorre, Harald Huebner, Dorothee Weikert, Jeanette Rientjes, Nicholas A. Veldhuis, Daniel P. Poole, Dane D. Jensen, Alex R. B. Thomsen, Brian L. Schmidt, Wendy L. Imlach, Peter Gmeiner, Nigel W. Bunnett
Summary: The hypothesis that sustained GPCR signaling from endosomes mediates pain is supported by the finding that specific GPCR antagonists can inhibit endosomal signals and relieve pain. The role of natural GPCR variants in pain maintenance is also explored. It is discovered that substance P can induce the assembly of endosomal signaling complexes, and that sustained inhibition of endosomal signals leads to long-lasting antinociceptive effects. These findings provide insight into the potential treatment strategies for diverse diseases involving GPCR signaling in intracellular locations.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Review
Chemistry, Medicinal
Ningning Sun, Kyeong-Man Kim
Summary: The desensitization of G protein-coupled receptors can occur through various mechanisms including phosphorylation-dependent desensitization at the receptor level and downstream mechanisms involving the sequestration of G proteins. These mechanisms involve GRKs, arrestins, and deubiquitinated arrestins to regulate GPCR signaling and prevent G-protein activation. Further studies are needed on the interesting mechanism of arrestin deubiquitination in GPCR desensitization.
ARCHIVES OF PHARMACAL RESEARCH
(2021)
Article
Biology
Benjamin Barsi-Rhyne, Aashish Manglik, Mark von Zastrow
Summary: Beta-arrestins are important regulators of cellular signaling, involving in the desensitization and endocytosis of GPCRs. Two different modes of endocytic activity have been discovered, one dependent on the C-terminus and the other dependent on the C-lobe of beta-arrestins. These modes are triggered in a receptor-specific manner and have opposite effects on the signaling output of receptors.