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

Bradley, S. J. et al. (2016) Mapping physiological G protein-coupled receptor signaling pathways reveals a role for receptor phosphorylation in airway contraction. Proceedings of the National Academy of Sciences of the United States of America, 113(16), pp. 4524-4529. (doi: 10.1073/pnas.1521706113) (PMID:27071102) (PMCID:PMC4843461)

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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 G(q/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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Bourgognon, Dr Julie-Myrtille and Tobin, Andrew and Bradley, Dr Sophie
Authors: Bradley, S. J., Wiegman, C. H., Iglesias, M. M., Kong, K. C., Butcher, A. J., Plouffe, B., Goupil, E., Bourgognon, J.-M., Macedo-Hatch, T., LeGouill, C., Russell, K., Laporte, S. A., König, G. M., Kostenis, E., Bouvier, M., Chung, K. F., Amrani, Y., and Tobin, A. B.
College/School:College of Medical Veterinary and Life Sciences > Institute of Molecular Cell and Systems Biology
College of Medical Veterinary and Life Sciences > Institute of Health and Wellbeing > Mental Health and Wellbeing
Journal Name:Proceedings of the National Academy of Sciences of the United States of America
Publisher:National Academy of Sciences
ISSN:0027-8424
ISSN (Online):1091-6490

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