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

• DOI: 10.1073/pnas.1521706113
• Publication Date: 2016-04-09T04:04:32Z
• Authors: Sophie J. Bradley; Coen H. Wiegman; Max Maza Iglesias; Kok Choi Kong; Adrian J. Butcher; Bianca Plouffe; Eugénie Goupil; Julie-Myrtille Bo...; 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
• Keywords: 0301 basic medicine; 570; muscarinic; Knockout; SMOOTH-MUSCLE-CELLS; CA2+ SENSITIVITY; 610; Bronchi; ACTIVATION; Mice; 03 medical and health sciences; LUNG SLICES; HYPERRESPONSIVENESS; Animals; Humans; G protein-coupled receptor; LIVING CELLS; Phosphorylation; Mice, Knockout; Receptor, Muscarinic M3; Science & Technology; INSULIN-RELEASE; Muscle, Smooth; MUSCARINIC ACETYLCHOLINE-RECEPTOR; asthma; ligand bias; 3. Good health; Multidisciplinary Sciences; Muscarinic M3; Muscle; Science & Technology - Other Topics; ASTHMA; Smooth; RHO-KINASE; signaling; Receptor; Signal Transduction

SignificanceStudies in transfected cells have established that G protein-coupled receptors (GPCRs) activate a number of intracellular signaling pathways; however, which of these pathways are physiologically important is unclear. Here, we use a genetically engineered mouse to demonstrate a novel role for M3-muscarinic acetylcholine receptor (M3-mAChR) phosphorylation in airway constriction, with implications for human respiratory disease, including asthma and chronic obstructive pulmonary disease. Combining this finding with other M3-mAChR physiological responses, we generate a map of responses that are downstream of G protein-dependent signaling or receptor phosphorylation-dependent signaling. Such a map predicts the outcome of biased GPCR drugs designed to drive receptor signaling preferentially toward pathways that improve therapeutic efficacy while minimizing toxic/adverse outcomes and provides a fundamental approach to the rational design of next-generation GPCR-based therapies.