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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.
Laporte, Stéphane A.
König, Gabriele M.
Chung, Kian Fan
Tobin, Andrew B.
|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.|
|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: http://creativecommons.org/licenses/by-nc-nd/4.0/|
|Appears in Collections:||Published Articles, Dept. of Infection, Immunity and Inflammation|
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|362486_1_uploaded_1454695489.pdf (Accepted Version).pdf||Post-review (final submitted)||9.98 MB||Adobe PDF||View/Open|
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