Article
Oncology
Caitrin Crudden, Takashi Shibano, Dawei Song, Mihnea P. Dragomir, Sonia Cismas, Julianna Serly, Daniela Nedelcu, Enrique Fuentes-Mattei, Andrei Tica, George A. Calin, Ada Girnita, Leonard Girnita
Summary: This study elucidates the molecular and biological roles of biased signaling downstream RTK, providing a novel approach to enhance the efficacy of anti-IGF1R-targeted therapy in cancer by targeting system bias. The findings suggest a promising strategy for the rational design or repurposing of therapeutics to selectively cross-target the IGF1R or other RTK.
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
Biochemistry & Molecular Biology
Leigh A. Stoddart, Laura E. Kilpatrick, Ross Corriden, Barrie Kellam, Stephen J. Briddon, Stephen J. Hill
Summary: The organization of G protein-coupled receptors at the plasma membrane has been a recent focus. Studies on the adenosine A(3) receptor and its mutant R108A reveal differences in membrane organization and downstream signaling, but both receptors can recruit beta-arrestin upon agonist stimulation, showing that effective G protein signaling is not necessary for membrane reorganization and beta-arrestin recruitment.
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)
Article
Biochemistry & Molecular Biology
Eleonore W. E. Verweij, Reggie Bosma, Meichun Gao, Jelle van den Bor, Betty Al Araaj, Sabrina M. de Munnik, Xiaoyuan Ma, Rob Leurs, Henry F. Vischer
Summary: This study used bioluminescence resonance energy transfer (BRET)-based biosensors to measure the effects of different agonists on the H1R signaling pathway, and found that one of the agonists exhibited biased agonism.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Multidisciplinary Sciences
Jeffrey S. Smith, Thomas F. Pack, Asuka Inoue, Claudia Lee, Kevin Zheng, Issac Choi, Dylan S. Eiger, Anmol Warman, Xinyu Xiong, Zhiyuan Ma, Gayathri Viswanathan, Ian M. Levitan, Lauren K. Rochelle, Dean P. Staus, Joshua C. Snyder, Alem W. Kahsai, Marc G. Caron, Sudarshan Rajagopal
Summary: This study demonstrates that GPCRs can facilitate a direct interaction between G(alpha i) protein family members and beta-arrestins, regardless of their classical G(alpha) protein subtype coupling. These findings introduce a novel GPCR signaling mechanism that is distinct from canonical G protein activation.
Article
Multidisciplinary Sciences
Eunna Huh, Jonathan Gallion, Melina A. Agosto, Sara J. Wright, Theodore G. Wensel, Olivier Lichtarge
Summary: The study suggests that somatic mutations across class A GPCRs are nonrandomly distributed, with impactful, recurrent mutations at selected positions of functional motifs. These mutations induce perturbation of G protein activation and/or beta-arrestin recruitment in multiple receptors, promoting tumor growth or survival. The findings open a window into cancer mechanisms and potential therapeutic approaches by revealing that multiple GPCRs can drive or enable cancer through mutations at cognate positions across GPCR paralogs.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Review
Cell Biology
Marta Lagana, Geraldine Schlecht-Louf, Francoise Bachelerie
Summary: GRKs not only regulate GPCR desensitization, but also act as scaffolds and signaling adapters in complex signaling networks that affect immune cell migration. The coordinated docking of multiple GRKs on an active chemokine receptor determines a specific receptor phosphorylation barcode that translates into different signaling and migration outcomes.
Article
Biochemistry & Molecular Biology
Melissa Girard, Steve Dagenais Bellefeuille, Emilie Eiselt, Guillaume Arguin, Jean-Michel Longpre, Philippe Sarret, Fernand-Pierre Gendron
Summary: This study found that endosomal trafficking plays an important role in G protein-coupled receptor (GPCR) signaling. UDP selectively activates GPCR P2Y6 as a signaling molecule. The study found that MRS2693 and UDP have different effects on the internalization of the P2Y6 receptor, with MRS2693 inducing P2Y6 internalization through an independent caveolin-dependent mechanism. This study provides insights for the development of bias ligands that can influence P2Y6 signaling.
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
(2023)
Review
Medicine, Research & Experimental
Juan Carlos Martinez-Morales, K. Helivier Solis, M. Teresa Romero-Avila, Guadalupe Reyes-Cruz, J. Adolfo Garcia-Sainz
Summary: G protein-coupled receptors (GPCRs) are membrane proteins that function as sensors and play significant roles in various physiological and pathological processes. This review provides an overview of the current understanding of the structure, signaling, internalization, and recycling of GPCRs.
ARCHIVES OF MEDICAL RESEARCH
(2022)
Article
Neurosciences
Sam R. J. Hoare, Paul H. Tewson, Shivani Sachdev, Mark Connor, Thomas E. Hughes, Anne Marie Quinn
Summary: Neurons integrate inputs over different time and space scales, combining fast and slow signals to produce behavior. Measuring signaling kinetics in live cells using fluorescent biosensors and dyes provides a deeper understanding of G-protein-coupled receptor signaling and therapeutic mechanisms in the nervous system.
FRONTIERS IN CELLULAR NEUROSCIENCE
(2022)
Review
Pharmacology & Pharmacy
Ee Von Moo, Jeffrey R. van Senten, Hans Brauner-Osborne, Thor C. Moller
Summary: This article discusses the importance of agonist-induced endocytosis in regulating cell surface receptor density and signaling. While arrestins are key regulators in GPCR internalization, there are also independent endocytosis pathways for GPCRs, expanding the diversity of the process.
MOLECULAR PHARMACOLOGY
(2021)
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
Matej Gazdarica, Judith Noda, Oleh Durydivka, Vendula Novosadova, Ken Mackie, Jean-Philippe Pin, Laurent Prezeau, Jaroslav Blahos
Summary: CB1R signaling is regulated by receptor desensitization and the protein SGIP1, which plays an important role in controlling CB1R function and its involvement in pathological conditions.
JOURNAL OF NEUROCHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
M. Claire Cato, Yu-Chen Yen, Charnelle J. Francis, Kaely E. Elkins, Afzaal Shareef, Rachel Sterne-Marr, John J. G. Tesmer
Summary: This paper discusses three distinct models for how GRKs recognize activated GPCRs, addresses limitations in the approaches used to generate them, and experimentally tests a hypothetical GPCR interaction site in GRK2 suggested by the two newest models.