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

Sophie J. Bradley, Coen H. Wiegman, Max Maza Iglesias, Kok Choi Kong, Adrian J. Butcher, Bianca Plouffe, Eugénie Goupil, Julie Myrtille Bourgognon, Timothy Macedo-Hatch, Christian Legouill, Kirsty Russell, Stéphane A. Laporte, Gabriele M. König, Evi Kostenis, Michel Bouvier, Kian Fan Chung, Yassine Amrani, Andrew B. Tobin*

*Corresponding author for this work

Research output: Contribution to journalArticle

23 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)4524-4529
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number16
Early online date08 Apr 2016
DOIs
Publication statusPublished - 19 Apr 2016
Externally publishedYes

Keywords

  • Asthma
  • G protein-coupled receptor
  • Ligand bias
  • Muscarinic
  • Signaling

ASJC Scopus subject areas

  • General

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    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., & Tobin, A. B. (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), 4524-4529. https://doi.org/10.1073/pnas.1521706113