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


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.

SUBMITTER: Bradley SJ 

PROVIDER: S-EPMC4843461 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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

Bradley Sophie J SJ   Wiegman Coen H CH   Iglesias Max Maza MM   Kong Kok Choi KC   Butcher Adrian J AJ   Plouffe Bianca B   Goupil Eugénie E   Bourgognon Julie-Myrtille JM   Macedo-Hatch Timothy T   LeGouill Christian C   Russell Kirsty K   Laporte Stéphane A SA   König Gabriele M GM   Kostenis Evi E   Bouvier Michel M   Chung Kian Fan KF   Amrani Yassine Y   Tobin Andrew B AB  

Proceedings of the National Academy of Sciences of the United States of America 20160408 16


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  ...[more]

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