Recent work by STRAND Member Kok Choi Kong has been published in the prestigious Proceedings of the National Academy of Sciences of the United States of America. The paper is important as studies 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. The authors 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, the authors also generate a map of responses that are downstream of G protein-dependent signaling or receptor phosphorylation-dependent signaling. This 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 providing a fundamental approach to the rational design of next-generation GPCR-based therapies.
If you are interested in the paper, the reference can be found below:
Bradley, SJ, Wiegman CHC, Iglesias, MM, Kong KC, Butcher AJ, Goupil E, Bourgognon JM, Macedo-Hatch T, Russell K, Laporte SA, Kostenis E, Bouvier M, Chung KF, Amrani Y, Tobin AB (2016): Mapping physiological G protein-coupled receptor signalling pathways reveals role for receptor phosphorylation in airway contraction. Proc Natl Acad Sci U S A 113 (16), 4524-4529