Mapping physiological G protein-coupled receptor signaling pathways reveals a role for receptor phosphorylation in airway contraction

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...

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Published in:Proceedings of the National Academy of Sciences - PNAS 2016-04, Vol.113 (16), p.4524-4529
Main Authors: Bradley, Sophie J., Wiegman, Coen H., Iglesias, Max Maza, Kong, Kok Choi, Butcher, Adrian J., Plouffe, Bianca, Goupil, Eugénie, Bourgognon, Julie-Myrtille, Macedo-Hatch, Timothy, LeGouill, Christian, Russell, Kirsty, Laporte, Stéphane A., König, Gabriele M., Kostenis, Evi, Bouvier, Michel, Chung, Kian Fan, Amrani, Yassine, Tobin, Andrew B.
Format: Article
Language:English
Subjects:
Animals
Biological Sciences
Bronchi - cytology
Bronchi - metabolism
Humans
Mice
Mice, Knockout
Muscle, Smooth - cytology
Muscle, Smooth - metabolism
Phosphorylation
Phosphorylation - physiology
Proteins
Receptor, Muscarinic M3 - genetics
Receptor, Muscarinic M3 - metabolism
Rodents
Signal transduction
Signal Transduction - physiology
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Summary: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:0027-8424
1091-6490
DOI:10.1073/pnas.1521706113