| First Author | Wang WC | Year | 2014 |
| Journal | Am J Physiol Lung Cell Mol Physiol | Volume | 307 |
| Issue | 10 | Pages | L775-80 |
| PubMed ID | 25260754 | Mgi Jnum | J:222190 |
| Mgi Id | MGI:5644107 | Doi | 10.1152/ajplung.00209.2014 |
| Citation | Wang WC, et al. (2014) Targeted transgenesis identifies Galphas as the bottleneck in beta2-adrenergic receptor cell signaling and physiological function in airway smooth muscle. Am J Physiol Lung Cell Mol Physiol 307(10):L775-80 |
| abstractText | G protein-coupled receptors are the most pervasive signaling superfamily in the body and act as receptors to endogenous agonists and drugs. For beta-agonist-mediated bronchodilation, the receptor-G protein-effector network consists of the beta2-adrenergic receptor (beta2AR), 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 Galphas in transgenic mice and found that agonist-promoted relaxation of airways was enhanced in direct proportion to the level of Galphas expression. Contraction of ASM from acetylcholine was not affected in Galphas transgenic mice, nor was relaxation by bitter taste receptors. Furthermore, agonist-promoted (but not basal) cAMP production in ASM cells from Galphas-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 Galphas mouse ASM. The enhanced maximal beta-agonist response was of similar magnitude for relaxation, cAMP production, and growth inhibition. Taken together, it appears that a limiting factor in beta-agonist responsiveness in ASM is the expression level of Galphas. Gene therapy or pharmacological means of increasing Galphas (or its coupling efficiency to beta2AR) thus represent an interface for development of novel therapeutic agents for improvement of beta-agonist therapy. |
