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

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Bradley, Sophie J 
Wiegman, Coen H 
Iglesias, Max Maza 
Kong, Kok Choi 
Butcher, Adrian J 


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.



G protein-coupled receptor, asthma, ligand bias, muscarinic, signaling, Animals, Bronchi, Humans, Mice, Mice, Knockout, Muscle, Smooth, Phosphorylation, Receptor, Muscarinic M3, Signal Transduction

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Proceedings of the National Academy of Sciences of USA

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National Academy of Sciences


Publisher's own licence
European Commission (10501)
This study is funded by the Medical Research Council (MRC) through funding of program leaders provided by the MRC Toxicology Unit (to A.B.T.).