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Proc Natl Acad Sci U S A. 2016 Apr 19;113(16):4524-9. doi: 10.1073/pnas.1521706113. Epub 2016 Apr 8.

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

Author information

1
Medical Research Council Toxicology Unit, University of Leicester, Leicester LE1 9HN, United Kingdom; Institute of Molecular Cell and Systems Biology, University of Glasgow, Glasgow G12 8QQ, United Kingdom;
2
Airway Disease Section, National Heart & Lung Institute, Imperial College London, London SW3 6LY, United Kingdom;
3
Department of Infection, Immunity, and Inflammation, Maurice Shock Medical Sciences Building, University of Leicester, Leicester LE1 9HN, United Kingdom;
4
School of Health Sciences, University of Brighton, Brighton BN2 4GL, United Kingdom;
5
Institute for Research in Immunology and Cancer, Department of Biochemistry and Molecular Medicine, Université de Montréal, Montreal, QC, Canada H3C 3J7;
6
Department of Medicine, McGill University, Montreal, QC, Canada H3A 2B2;
7
Medical Research Council Toxicology Unit, University of Leicester, Leicester LE1 9HN, United Kingdom;
8
Department of Pharmacy, University of Bonn, 53115 Bonn, Germany.
9
Department of Infection, Immunity, and Inflammation, Maurice Shock Medical Sciences Building, University of Leicester, Leicester LE1 9HN, United Kingdom; ya26@le.ac.uk tba@le.ac.uk.
10
Medical Research Council Toxicology Unit, University of Leicester, Leicester LE1 9HN, United Kingdom; Institute of Molecular Cell and Systems Biology, University of Glasgow, Glasgow G12 8QQ, United Kingdom; ya26@le.ac.uk tba@le.ac.uk.

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.

KEYWORDS:

G protein-coupled receptor; asthma; ligand bias; muscarinic; signaling

PMID:
27071102
PMCID:
PMC4843461
DOI:
10.1073/pnas.1521706113
[Indexed for MEDLINE]
Free PMC Article

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