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

Bradley SJ, Wiegman CH, Iglesias MM, Kong KC, Butcher AJ, Plouffe B, Goupil E, Bourgognon JM, Macedo-Hatch T, LeGouill C, Russell K, Laporte SA, König GM, Kostenis E, Bouvier M, Chung KF, Amrani Y, Tobin AB

Medical Research Council Toxicology Unit, University of Leicester, Leicester LE1 9HN, United Kingdom; Institute of Molecular Cell and Systems Biology, University of Glasgow, Glasgow G12 8QQ, United Kingdom;

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.

Proc. Natl. Acad. Sci. U.S.A. 2016;113(16):4524-9.

Pubmed ID: 27071102

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