Targeted transgenesis identifies G^sub [alpha]s^ as the bottleneck in [Beta]^sub 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 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 Gas in transgenic mice and found that agonist-promoted relaxation of airways was enhanced in direct proportion to the level of Gas expression. Contraction of ASM from acetylcholine was not affected in Gas transgenic mice, nor was relaxation by bitter taste receptors. Furthermore, agonist-promoted (but not basal) cAMP production in ASM cells from Gas-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 Gas 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 Gas. Gene therapy or pharmacological means of increasing Gas (or its coupling efficiency to β2AR) thus represent an interface for development of novel therapeutic agents for improvement of β-agonist therapy.