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

被引:39
作者
Bradley, Sophie J. [1 ,2 ]
Wiegman, Coen H. [3 ]
Iglesias, Max Maza [4 ]
Kong, Kok Choi [5 ]
Butcher, Adrian J. [1 ,2 ]
Plouffe, Bianca [6 ]
Goupil, Eugenie [7 ]
Bourgognon, Julie-Myrtille [1 ]
Macedo-Hatch, Timothy [1 ]
LeGouill, Christian [6 ]
Russell, Kirsty [3 ]
Laporte, Stephane A. [7 ]
Koenig, Gabriele M. [8 ]
Kostenis, Evi [8 ]
Bouvier, Michel [6 ]
Chung, Kian Fan [3 ]
Amrani, Yassine [4 ]
Tobin, Andrew B. [1 ,2 ]
机构
[1] Univ Leicester, MRC, Toxicol Unit, Leicester LE1 9HN, Leics, England
[2] Univ Glasgow, Inst Mol Cell & Syst Biol, Glasgow G12 8QQ, Lanark, Scotland
[3] Univ London Imperial Coll Sci Technol & Med, Airway Dis Sect, Natl Heart & Lung Inst, London SW3 6LY, England
[4] Univ Leicester, Dept Infect Immun & Inflammat, Maurice Shock Med Sci Bldg, Leicester LE1 9HN, Leics, England
[5] Univ Brighton, Sch Hlth Sci, Brighton BN2 4GL, E Sussex, England
[6] Univ Montreal, Inst Res Immunol & Canc, Dept Biochem & Mol Med, Montreal, PQ H3C 3J7, Canada
[7] McGill Univ, Dept Med, Montreal, PQ H3A 2B2, Canada
[8] Univ Bonn, Dept Pharm, D-53115 Bonn, Germany
基金
加拿大健康研究院; 英国医学研究理事会;
关键词
G protein-coupled receptor; asthma; muscarinic; ligand bias; signaling; MUSCARINIC ACETYLCHOLINE-RECEPTOR; SMOOTH-MUSCLE-CELLS; RHO-KINASE; CA2+ SENSITIVITY; INSULIN-RELEASE; ACTIVATION; HYPERRESPONSIVENESS; DISSOCIATION; INFLAMMATION; INHALATION;
D O I
10.1073/pnas.1521706113
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
引用
收藏
页码:4524 / 4529
页数:6
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