Mapping physiological G protein-coupled receptor signaling pathways reveals a role for receptor phosphorylation in airway contraction
Proc Natl Acad Sci U S A. 2016 Apr 19;113(16):4524-9. doi: 10.1073/pnas.1521706113. Epub 2016 Apr 8.
Sophie J Bradley 1, Coen H Wiegman 2, Max Maza Iglesias 3, Kok Choi Kong 4, Adrian J Butcher 1, Bianca Plouffe 5, Eugénie Goupil 6, Julie-Myrtille Bourgognon 7, Timothy Macedo-Hatch 7, Christian LeGouill 5, Kirsty Russell 2, Stéphane A Laporte 6, Gabriele M König 8, Evi Kostenis 8, Michel Bouvier 5, Kian Fan Chung 2, Yassine Amrani 9, Andrew B Tobin 10
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.