Targeted transgenesis identifies G αs as the bottleneck in β 2 -adrenergic receptor cell signaling and physiological function in airway smooth muscle

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 β 2 -adrenergic receptor (β 2 AR), G s , 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 G αs in transgenic mice and found that agonist-promoted relaxation of airways was enhanced in direct proportion to the level of G αs expression. Contraction of ASM from acetylcholine was not affected in G αs transgenic mice, nor was relaxation by bitter taste receptors. Furthermore, agonist-promoted (but not basal) cAMP production in ASM cells from G αs -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 G αs 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 G αs . Gene therapy or pharmacological means of increasing G αs (or its coupling efficiency to β 2 AR) thus represent an interface for development of novel therapeutic agents for improvement of β-agonist therapy.