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Title: Mapping physiological G protein-coupled receptor signaling pathways reveals a role for receptor phosphorylation in airway contraction
Authors: Bradleya, 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.
First Published: 8-Apr-2016
Publisher: National Academy of Sciences
Citation: Proceedings of the National Academy of Sciences of USA (Early Edition)
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.
DOI Link: 10.1073/pnas.1521706113
eISSN: 1091-6490
Version: Post-print
Status: Peer-reviewed
Type: Journal Article
Rights: Copyright © 2016 PNAS. The file associated with this record is distributed under the Creative Commons “Attribution Non-Commercial No Derivatives” licence, further details of which can be found via the following link:
Appears in Collections:Published Articles, Dept. of Infection, Immunity and Inflammation

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