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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Legouill, Christian Iglesias, Max Maza Goupil, Eugénie Bourgognon, Julie-myrtille Chung, Kian Fan Laporte, Stéphane A. Macedo-hatch, Timothy Tobin, Andrew B. Russell, Kirsty Wiegman, Coen H. Butcher, Adrian J. König, Gabriele M. Bouvier, Michel Kostenis, Evi Amrani, Yassine Kong, Kok Choi Plouffe, Bianca Bradley, Sophie J. |
| Description | Author Affiliation: Bradley SJ ( Medical Research Council Toxicology Unit, University of Leicester, Leicester LE1 9HN, United Kingdom); Wiegman CH ( Airway Disease Section, National Heart & Lung Institute, Imperial College London, London SW3 6LY, United Kingdom); Iglesias MM ( Department of Infection, Immunity, and Inflammation, Maurice Shock Medical Sciences Building, University of Leicester, Leicester LE1 9HN, United Kingdom); Kong KC ( School of Health Sciences, University of Brighton, Brighton BN2 4GL, United Kingdom); Butcher AJ ( Medical Research Council Toxicology Unit, University of Leicester, Leicester LE1 9HN, United Kingdom); Plouffe B ( Institute for Research in Immunology and Cancer, Department of Biochemistry and Molecular Medicine, Université de Montréal, Montreal, QC, Canada H3C 3J7); Goupil E ( Department of Medicine, McGill University, Montreal, QC, Canada H3A 2B2); Bourgognon JM ( Medical Research Council Toxicology Unit, University of Leicester, Leicester LE1 9HN, United Kingdom); Macedo-Hatch T ( Medical Research Council Toxicology Unit, University of Leicester, Leicester LE1 9HN, United Kingdom); LeGouill C ( Institute for Research in Immunology and Cancer, Department of Biochemistry and Molecular Medicine, Université de Montréal, Montreal, QC, Canada H3C 3J7); Russell K ( Airway Disease Section, National Heart & Lung Institute, Imperial College London, London SW3 6LY, United Kingdom); Laporte SA ( Department of Medicine, McGill University, Montreal, QC, Canada H3A 2B2); König GM ( Department of Pharmacy, University of Bonn, 53115 Bonn, Germany.); Kostenis E ( Department of Pharmacy, University of Bonn, 53115 Bonn, Germany.); Bouvier M ( Institute for Research in Immunology and Cancer, Department of Biochemistry and Molecular Medicine, Université de Montréal, Montreal, QC, Canada H3C 3J7); Chung KF ( Airway Disease Section, National Heart & Lung Institute, Imperial College London, London SW3 6LY, United Kingdom); Amrani Y ( Department of Infection, Immunity, and Inflammation, Maurice Shock Medical Sciences Building, University of Leicester, Leicester LE1 9HN, United Kingdom); Tobin AB ( Medical Research Council Toxicology Unit, University of Leicester, Leicester LE1 9HN, United Kingdom); |
| Abstract | G protein-coupled receptors (GPCRs) are known to initiate a plethora of signaling pathways in vitro. However, it is unclear which of these pathways are engaged to mediate physiological responses. Here, we examine the distinct roles of Gq/11-dependent signaling and receptor phosphorylation-dependent signaling in bronchial airway contraction and lung function regulated through the M3-muscarinic acetylcholine receptor (M3-mAChR). By using a genetically engineered mouse expressing a G protein-biased M3-mAChR mutant, we reveal the first evidence, to our knowledge, of a role for M3-mAChR phosphorylation in bronchial smooth muscle contraction in health and in a disease state with relevance to human asthma. Furthermore, this mouse model can be used to distinguish the physiological responses that are regulated by M3-mAChR phosphorylation (which include control of lung function) from those responses that are downstream of G protein signaling. In this way, we present an approach by which to predict the physiological/therapeutic outcome of M3-mAChR-biased ligands with important implications for drug discovery. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 16 |
| Volume Number | 113 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2016-04-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Bronchi Metabolism Muscle, Smooth Receptor, Muscarinic M3 Signal Transduction Physiology Animals Cytology Mice Mice, Knockout Phosphorylation Genetics Research Support, Non-U.S. Gov't Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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