title: Targeted transgenesis identifies Gαs as the bottleneck in β2-adrenergic receptor cell signaling and physiological function in airway smooth muscle.
abstract: G protein-coupled receptors are the most pervasive signaling superfamily in the body and act as receptors to endogenous agonists and drugs. For β-agonist-mediated bronchodilation, the receptor-G protein-effector network consists of the β2-adrenergic receptor (β2AR), Gs, and adenylyl cyclase, expressed on airway smooth muscle (ASM). Using ASM-targeted transgenesis, we previously explored which of these three early signaling elements represents a limiting factor, or bottleneck, in transmission of the signal from agonist binding to ASM relaxation. Here we overexpressed Gαs in transgenic mice and found that agonist-promoted relaxation of airways was enhanced in direct proportion to the level of Gαs expression. Contraction of ASM from acetylcholine was not affected in Gαs transgenic mice, nor was relaxation by bitter taste receptors. Furthermore, agonist-promoted (but not basal) cAMP production in ASM cells from Gαs-transgenic mice was enhanced compared with ASM from nontransgenic littermates. Agonist-promoted inhibition of platelet-derived growth factor-stimulated ASM proliferation was also enhanced in Gαs mouse ASM. The enhanced maximal β-agonist response was of similar magnitude for relaxation, cAMP production, and growth inhibition. Taken together, it appears that a limiting factor in β-agonist responsiveness in ASM is the expression level of Gαs. Gene therapy or pharmacological means of increasing Gαs (or its coupling efficiency to β2AR) thus represent an interface for development of novel therapeutic agents for improvement of β-agonist therapy.
authors.affiliation: Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland;
authors.forename: Wayne C H
authors.initials: WC
authors.lastname: Wang
authors.affiliation: Department of Medicine, University of South Florida Morsani College of Medicine, Tampa, Florida; Center for Personalized Medicine and Genomics, University of South Florida Morsani College of Medicine, Tampa, Florida;
authors.forename: Susan H
authors.initials: SH
authors.lastname: Pauer
authors.affiliation: Department of Medicine, University of South Florida Morsani College of Medicine, Tampa, Florida; Center for Personalized Medicine and Genomics, University of South Florida Morsani College of Medicine, Tampa, Florida;
authors.forename: Dan'elle C
authors.initials: DC
authors.lastname: Smith
authors.affiliation: Department of Medicine, University of South Florida Morsani College of Medicine, Tampa, Florida; Center for Personalized Medicine and Genomics, University of South Florida Morsani College of Medicine, Tampa, Florida;
authors.forename: Madison A
authors.initials: MA
authors.lastname: Dixon
authors.affiliation: Department of Medicine, University of South Florida Morsani College of Medicine, Tampa, Florida; Center for Personalized Medicine and Genomics, University of South Florida Morsani College of Medicine, Tampa, Florida;
authors.forename: David J
authors.initials: DJ
authors.lastname: Disimile
authors.affiliation: Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland;
authors.forename: Alfredo
authors.initials: A
authors.lastname: Panebra
authors.affiliation: Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland; and.
authors.forename: Steven S
authors.initials: SS
authors.lastname: An
authors.affiliation: Department of Medicine, University of South Florida Morsani College of Medicine, Tampa, Florida; Center for Personalized Medicine and Genomics, University of South Florida Morsani College of Medicine, Tampa, Florida;
authors.forename: Blanca
authors.initials: B
authors.lastname: Camoretti-Mercado
authors.affiliation: Department of Medicine, University of South Florida Morsani College of Medicine, Tampa, Florida; Center for Personalized Medicine and Genomics, University of South Florida Morsani College of Medicine, Tampa, Florida; Department of Molecular Pharmacology and Physiology, University of South Florida Morsani College of Medicine, Tampa, Florida sliggett@health.usf.edu.
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Liggett
mesh_terms: D058666:Adrenergic beta-2 Receptor Agonists / Q000494:pharmacology; D000818:Animals; D001993:Bronchodilator Agents / Q000494:pharmacology; D002460:Cell Line; D044385:GTP-Binding Protein alpha Subunits / Q000096:biosynthesis* / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009130:Muscle, Smooth / Q000378:metabolism* / Q000473:pathology; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics / Q000378:metabolism*; D012137:Respiratory System / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D001993:Bronchodilator Agents; D044385:GTP-Binding Protein alpha Subunits; D018343:Receptors, Adrenergic, beta-2
keywords: bronchodilation; relaxation; stoichiometry; β-agonist