362486_1_uploaded_1454695489 (Accepted Version).pdf.pdf (9.75 MB)
Mapping physiological G protein-coupled receptor signaling pathways reveals a role for receptor phosphorylation in airway contraction
journal contributionposted on 2016-04-14, 08:42 authored by Sophie J. Bradleya, 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
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.
CitationProceedings of the National Academy of Sciences of USA (Early Edition)
Author affiliation/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/School of Medicine/Department of Infection, Immunity and Inflammation
- AM (Accepted Manuscript)