title: G Protein βγ-subunit signaling mediates airway hyperresponsiveness and inflammation in allergic asthma.
abstract: Since the Gβγ subunit of Gi protein has been importantly implicated in regulating immune and inflammatory responses, this study investigated the potential role and mechanism of action of Gβγ signaling in regulating the induction of airway hyperresponsiveness (AHR) in a rabbit model of allergic asthma. Relative to non-sensitized animals, OVA-sensitized rabbits challenged with inhaled OVA exhibited AHR, lung inflammation, elevated BAL levels of IL-13, and increased airway phosphodiesterase-4 (PDE4) activity. These proasthmatic responses were suppressed by pretreatment with an inhaled membrane-permeable anti-Gβγ blocking peptide, similar to the suppressive effect of glucocorticoid pretreatment. Extended mechanistic studies demonstrated that: 1) corresponding proasthmatic changes in contractility exhibited in isolated airway smooth muscle (ASM) sensitized with serum from OVA-sensitized+challenged rabbits or IL-13 were also Gβγ-dependent and mediated by MAPK-upregulated PDE4 activity; and 2) the latter was attributed to Gβγ-induced direct stimulation of the non-receptor tyrosine kinase, c-Src, resulting in downstream activation of ERK1/2 and its consequent transcriptional upregulation of PDE4. Collectively, these data are the first to identify that a mechanism involving Gβγ-induced direct activation of c-Src, leading to ERK1/2-mediated upregulation of PDE4 activity, plays a decisive role in regulating the induction of AHR and inflammation in a rabbit model of allergic airway disease.
authors.affiliation: Division of Pulmonary Medicine, Children's Hospital of Philadelphia Research Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States of America.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Nino
authors.forename: Aihua
authors.initials: A
authors.lastname: Hu
authors.forename: Judith S
authors.initials: JS
authors.lastname: Grunstein
authors.forename: Joseph
authors.initials: J
authors.lastname: McDonough
authors.forename: Portia A
authors.initials: PA
authors.lastname: Kreiger
authors.forename: Maureen B
authors.initials: MB
authors.lastname: Josephson
authors.forename: John K
authors.initials: JK
authors.lastname: Choi
authors.forename: Michael M
authors.initials: MM
authors.lastname: Grunstein
mesh_terms: D000818:Animals; D001249:Asthma / Q000378:metabolism*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism; D044387:GTP-Binding Protein beta Subunits / Q000378:metabolism*; D044388:GTP-Binding Protein gamma Subunits / Q000378:metabolism*; D006801:Humans; D006967:Hypersensitivity / Q000378:metabolism*; D006969:Hypersensitivity, Immediate / Q000378:metabolism*; D007249:Inflammation; D020935:MAP Kinase Signaling System; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D008954:Models, Biological; D009130:Muscle, Smooth / Q000166:cytology; D010047:Ovalbumin / Q000378:metabolism; D011817:Rabbits; D012137:Respiratory System / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic
chemical_list: C118981:G-protein Beta gamma; D044387:GTP-Binding Protein beta Subunits; D044388:GTP-Binding Protein gamma Subunits; D010047:Ovalbumin; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4