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)
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
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
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
Biochemistry & Molecular Biology
Kiae Kim, Yeonjin Han, Longhan Duan, Ka Young Chung
Summary: Beta-arrestins are proteins initially identified for desensitizing and internalizing G-protein-coupled receptors (GPCRs). By scaffolding MAPK signaling components, beta-arrestins initiate a second wave of signaling, promoting the activation of ERK1/2 or JNK3. Understanding the molecular and structural mechanisms of beta-arrestin-mediated MAPK scaffolding assembly is crucial for understanding GPCR-mediated MAPK activation and selectively regulating the MAPK signaling cascade for therapeutic purposes.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Dike Qiu, Ke Xu, Namjin Chung, Jennifer Robbins, Robert Luo, Michael Lawrence, Aiqing He, Fei Yu, Andrew Alt, Michael M. Miller, Jon Hangeland, John N. Feder, Dietmar Seiffert, Brian J. Arey
Summary: Vascular endothelial cells are influenced by mechanical forces and the patterns of these forces can regulate endothelial cell function and cardiovascular health. The transcription factor KLF2 plays a key role in the positive effects of laminar flow patterns on endothelial cell phenotype. Identifying endothelial regulators of the KLF2 program could lead to new therapeutic approaches for treating cardiovascular disease. GPCR targets that modulate KLF2 expression were identified through genetic screening, and several GPCRs were found to affect KLF2 transcriptional activation. These targets could be potential candidates for novel treatments targeting the endothelium. Initiating drug discovery efforts for LGR4 and finding synthetic ligands for this receptor demonstrate the potential for identifying new drug targets through pathway-directed phenotypic screening.
FRONTIERS IN MOLECULAR BIOSCIENCES
(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
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)
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
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
Biochemistry & Molecular Biology
Marta Sanchez-Soto, Noelia M. Boldizsar, Kayla A. Schardien, Nora S. Madaras, Blair K. A. Willette, Laura R. Inbody, Christopher Dasaro, Amy E. Moritz, Julia Drube, Raphael S. Haider, R. Benjamin Free, Carsten Hoffman, David R. Sibley
Summary: The recruitment and activation of beta-arrestins to the D2 dopamine receptor (D2R) are not completely dependent on GPCR kinase (GRK)-mediated receptor phosphorylation, highlighting the importance of the GRK subfamily in D2R-beta-arrestin interactions.
Article
Cell Biology
Henk Karst, Femke S. den Boon, Niek Vervoort, Max Adrian, Lukas C. Kapitein, Marian Joels
Summary: The mineralocorticoid receptor (MR) in the mammalian brain mediates both genomic and non-genomic actions, possibly located near or translocated to the cell membrane. Although it is challenging to convincingly visualize membrane localization of endogenous MR or GFP-MR molecules, there is evidence suggesting that MR may be trafficked via beta-arrestin.
MOLECULAR AND CELLULAR ENDOCRINOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Amy E. Moritz, Nora S. Madaras, Michele L. Rankin, Laura R. Inbody, David R. Sibley
Summary: The D1 dopamine receptor can be phosphorylated by GRKs at multiple sites, including the C-terminus and the third intracellular loop. This phosphorylation regulates the sensitivity and internalization of the D1 dopamine receptor through the activation of β-arrestin.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Review
Pharmacology & Pharmacy
Hitoshi Kurose
Summary: It is well-established that GPCRs transduce signals into cells using G proteins. β-arrestins can also mediate signaling through GPCRs. Selective activation of signaling through G proteins or β-arrestins can be achieved using biased agonists. Biased agonists show promise for clinical use with potentially fewer side effects. The mechanism of G protein-biased agonists may involve partial agonists and appropriate assay systems should be considered.
YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN
(2022)
Article
Medicine, Research & Experimental
Emilie Heckel, Gael Cagnone, Tapan Agnihotri, Bertan Cakir, Ashim Das, Jin Sung Kim, Nicholas Kim, Genevieve Lavoie, Anu Situ, Sheetal Pundir, Ye Sun, Florian Wunnemann, Kerry A. Pierce, Courtney Dennis, Grant A. Mitchell, Sylvain Chemtob, Flavio A. Rezende, Gregor Andelfinger, Clary B. Clish, Philippe P. Roux, Przemyslaw Sapieha, Lois Eh Smith, Jean-Sebastien Joyal
Summary: Dyslipidemia and autophagy play roles in the development of blinding neovascular age-related macular degeneration. Excess circulating lipids can inhibit retinal autophagy, leading to pathological angiogenesis. Restoring photoreceptor autophagy can enhance metabolic efficiency and suppress pathological angiogenesis.
Article
Biology
Alexander S. Hauser, Charlotte Avet, Claire Normand, Arturo Mancini, Asuka Inoue, Michel Bouvier, David E. Gloriam
Summary: Two-thirds of human hormones and one-third of clinical drugs act on membrane receptors coupled to G proteins, but there are differences in the reported G protein couplings among recent large-scale datasets. This study presents a common coupling map that uncovers novel couplings, GPCR-G protein selectivity, and the comparison of co-coupling and co-expression of G proteins with phylogenetic relationships. These findings will advance receptor research and cellular signaling, and contribute to the development of safer drugs.
Article
Biology
Charlotte Avet, Arturo Mancini, Billy Breton, Christian Le Gouill, Alexander S. Hauser, Claire Normand, Hiroyuki Kobayashi, Florence Gross, Mireille Hogue, Viktoriya Lukasheva, Stephane St-Onge, Marilyn Carrier, Madeleine Heroux, Sandra Morissette, Eric B. Fauman, Jean-Philippe Fortin, Stephan Schann, Xavier Leroy, David E. Gloriam, Michel Bouvier
Summary: This study presents a set of BRET sensors to monitor the activation of G protein subtypes without modifying the receptors or G proteins. Profiling 100 therapeutically relevant human GPCRs resulted in pathway-specific concentration-response curves, revealing a diversity of coupling profiles.
Article
Endocrinology & Metabolism
Stefano Marullo, Mark G. H. Scott, Herve Enslen, Mathieu Coureuil
Summary: This perspective article summarizes the research on the signalling cascades induced by meningococcus in host cells, revealing the important role of the β(2)-adrenergic receptor as the receptor involved. It also discovered the association between the early adhesion receptor CD147 and the cytoskeletal protein α-actinin 4.
FRONTIERS IN ENDOCRINOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Benoit Chevalier, Nesrine Baatallah, Matthieu Najm, Solene Castanier, Vincent Jung, Iwona Pranke, Anita Golec, Veronique Stoven, Stefano Marullo, Fabrice Antigny, Ida Chiara Guerrera, Isabelle Sermet-Gaudelus, Aleksander Edelman, Alexandre Hinzpeter
Summary: In this study, the interaction of CFTR and its mutants with other proteins was investigated using various experimental approaches. Proximity labeling methods based on TurboID and APEX2 were evaluated and compared to existing databases. The results revealed new protein partners and provided a more comprehensive understanding of the CFTR interactome.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Pharmacology & Pharmacy
Franziska Marie Heydenreich, Bianca Plouffe, Aurelien Rizk, Dalibor Milic, Joris Zhou, Billy Breton, Christian Le Gouill, Asuka Inoue, Michel Bouvier, Dmitry B. Veprintsev
Summary: By modeling G protein activation as a Michaelis-Menten reaction, we have developed a novel method for quantifying signaling bias. V2R activates, or at least engages, G proteins from all G protein subfamilies, including Gi2, Gz, Gq, G12, and G13. Their relative activation may explain its Gs-independent signaling.
MOLECULAR PHARMACOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Kusumika Saha, Benoit Chevalier, Stephane Doly, Nesrine Baatallah, Thomas Guilbert, Iwona Pranke, Mark G. H. Scott, Herve Enslen, Chiara Guerrera, Cerina Chuon, Aleksander Edelman, Isabelle Sermet-Gaudelus, Alexandre Hinzpeter, Stefano Marullo
Summary: The exit of certain plasma membrane proteins from the endoplasmic reticulum is regulated by arginine-based retention motifs. PRAF2, a gatekeeper protein, recognizes these motifs and retains specific proteins in the ER. It has been found that PRAF2 can interact with mutant CFTR, preventing it from reaching the ER exit sites. Pharmacological chaperones have also been shown to rescue CFTR-F508del retention by PRAF2 through various mechanisms. These findings provide new therapeutic perspectives for diseases caused by impaired cell surface trafficking of mutant proteins.
CELLULAR AND MOLECULAR LIFE SCIENCES
(2022)
Article
Chemistry, Medicinal
Wei Chen, Di Cui, Steven V. Jerome, Mayako Michino, Eelke B. Lenselink, David J. Huggins, Alexandre Beautrait, Jeremie Vendome, Robert Abel, Richard A. Friesner, Lingle Wang
Summary: In the hit identification stage of drug discovery, absolute protein-ligand binding free-energy perturbation (ABFEP) is a theoretically rigorous and accurate method that can greatly improve hit rates in virtual screening. In this work, an implementation of ABFEP method in FEP+ was described and validated using different compounds and protein receptors. The calculated binding free energies showed good correlation with experimental results and demonstrated the usefulness of ABFEP in improving hit rates in virtual screening.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2023)
Article
Oncology
Sherif Samer Attalla, Jonathan Boucher, Hailey Proud, Tarek Taifour, Dongmei Zuo, Virginie Sanguin-Gendreau, Chen Ling, Gabriella Johnson, Vincent Li, Robin B. Luo, Hellen Kuasne, Vasilios Papavasiliou, Logan A. Walsh, Mark Barok, Heikki Joensuu, Morag Park, Philippe P. Roux, William J. Muller
Summary: The tumor-immune microenvironment (TIME) plays a crucial role in therapeutic response, and this study reveals the association of HER2A16 variant with poor clinical outcome in breast cancer and the immune cold phenotype of HER2A16 tumors. ENPP1 is identified as a functional regulator of the immune cold microenvironment, and targeting ENPP1 may have therapeutic potential in aggressive HER2 positive breast cancer.
CANCER IMMUNOLOGY RESEARCH
(2023)
Article
Biochemistry & Molecular Biology
Valeria Burghi, Justine S. Paradis, Adam Officer, Sendi Rafael Adame-Garcia, Xingyu Wu, Edda S. F. Matthees, Benjamin Barsi-Rhyne, Dana J. Ramms, Lauren Clubb, Monica Acosta, Pablo Tamayo, Michel Bouvier, Asuka Inoue, Mark von Zastrow, Carsten Hoffmann, J. Silvio Gutkind
Summary: This study focuses on the role of beta-arrestins in G protein-coupled receptor (GPCR) signaling. It is found that while G proteins are essential for GPCR signaling, beta-arrestins play a more prominent role in signal compartmentalization and modulation of gene expression.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2023)
Article
Neurosciences
Aishwarya Mary Johnson, Sara Jose, Abdul Rasheed Palakkott, Farheen Badrealam Khan, Nanthini Jayabalan, Jaleel Kizhakkayil, Shamma Abdulla Ali AlNaqbi, Mark G. H. Scott, Mohammed Akli Ayoub, Richard Gordon, Hariharan Saminathan
Summary: Parkinson's disease is a progressive neurodegenerative disorder characterized by the degeneration of dopaminergic neurons. Fyn kinase activation has been identified as an early signaling event in PD, and PTEN may be the upstream regulator of Fyn activation. By modulating PTEN activity, dopaminergic neurons can be protected from neurotoxicity and mitochondrial dysfunction in PD.
JOURNAL OF NEUROIMMUNE PHARMACOLOGY
(2023)
Article
Multidisciplinary Sciences
Shane C. Wright, Aikaterini Motso, Stefania Koutsilieri, Christian M. Beusch, Pierre Sabatier, Alessandro Berghella, Elodie Blondel-Tepaz, Kimberley Mangenot, Ioannis Pittarokoilis, Despoina-Christina Sismanoglou, Christian Le Gouill, Jesper V. Olsen, Roman A. Zubarev, Nevin A. Lambert, Alexander S. Hauser, Michel Bouvier, Volker M. Lauschke
Summary: This study investigates the subcellular location of GLP-1R signaling events and reveals associations between signaling profiles and adverse drug reactions, providing important insights for rational drug design and improving the therapeutic potential of GLP-1R agonists.
NATURE COMMUNICATIONS
(2023)
Article
Multidisciplinary Sciences
Helene M. Roux, Amira Marouf, Jacques Dutrieux, Benedicte Charmeteau-De Muylder, Suzanne Figueiredo-Morgado, Veronique Avettand-Fenoel, Pelagia Cuvelier, Cecile Naudin, Fatma Bouaziz, Guillaume Geri, Anne Couedel-Courteille, Pierre Squara, Stefano Marullo, Remi Cheynier
Summary: Thymic activation improves the outcome of COVID-19 patients with severe pneumonia. Genetic polymorphism that affects thymic output can modify SARS-CoV-2 immunity and disease severity. GG genotype is associated with stronger and long-lasting immune response and less severe lung involvement.
Meeting Abstract
Hematology
Mathieu Roussy, Luc Boulianne, Nehme Hachem, Louis Theret, Verena Gress, Leo Aubert, Melanie Bilodeau, Sophie Cardin, Louise Laramee, Veronique Lisi, Alexandre Rouette, Philippe Roux, Vincent-Philippe Lavallee, Sonia Cellot
EXPERIMENTAL HEMATOLOGY
(2022)
Meeting Abstract
Endocrinology & Metabolism
F. abg Abou Azar, S. Allali, M. Abayomi, S. Yuen, S. Del Veliz, Y. Mugabo, F. Pare, G. Lavoie, P. P. Roux, G. E. Lim
