Paradoxical attenuation of β2-AR function in airway smooth muscle by Gi-mediated counterregulation in transgenic mice overexpressing type 5 adenylyl cyclase
| Autor: | Rachel M. Schillinger, Stephen B. Liggett, Wayne C. H. Wang, Molly M. Malone |
|---|---|
| Rok vydání: | 2011 |
| Předmět: |
Pulmonary and Respiratory Medicine
Genetically modified mouse medicine.medical_specialty Physiology Ratón Muscle Relaxation Transgene Myocytes Smooth Muscle Mice Transgenic GTP-Binding Protein alpha Subunits Gi-Go In Vitro Techniques Biology Adenylyl cyclase Mice chemistry.chemical_compound Enzyme activator Physiology (medical) Internal medicine Cyclic AMP medicine Animals Myocyte Extracellular Signal-Regulated MAP Kinases Receptor Adrenergic beta-2 Receptor Agonists Muscle Smooth Articles Cell Biology Rats Enzyme Activation Trachea Endocrinology Muscle relaxation chemistry Receptors Adrenergic beta-2 Adenylyl Cyclases |
| Zdroj: | American Journal of Physiology-Lung Cellular and Molecular Physiology. 300:L472-L478 |
| ISSN: | 1522-1504 1040-0605 |
| Popis: | The limiting component within the receptor-G protein-effector complex in airway smooth muscle (ASM) for β2-adrenergic receptor (β2-AR)-mediated relaxation is unknown. In cardiomyocytes, adenylyl cyclase (AC) is considered the “bottleneck” for β-AR signaling, and gene therapy trials are underway to increase inotropy by increasing cardiac AC expression. We hypothesized that increasing AC in ASM would increase relaxation from β-agonists, thereby providing a strategy for asthma therapy. Transgenic (TG) mice were generated with approximately two- to threefold overexpression of type 5 AC (AC5) in ASM. cAMP and airway relaxation in response to direct activation of AC by forskolin were increased in AC5-TG. Counter to our hypothesis, isoproterenol-mediated airway relaxation was significantly attenuated (∼50%) in AC5-TG, as was cAMP production, suggesting compensatory regulatory events limiting β2-AR signaling when AC expression is increased. In contrast, acetylcholine-mediated contraction was preserved. Gαiexpression and ERK1/2 activation were markedly increased in AC5-TG (5- and 8-fold, respectively), and β-AR expression was decreased by ∼40%. Other G proteins, G protein-coupled receptor kinases, and β-arrestins were unaffected. β-agonist-mediated airway relaxation of AC5-TG was normalized to that of nontransgenic mice by pertussis toxin, implicating β2-AR coupling to the increased Gias a mechanism of depressed agonist-promoted relaxation in these mice. The decrease in β2-AR may account for additional relaxation impairment, given that there is no enhancement over nontransgenic after pertussis toxin, despite AC5 overexpression. ERK1/2 inhibition had no effect on the phenotype. Thus perturbing the ratio of β2-AR to AC in ASM by increasing AC fails to improve (and actually decreases) β-agonist efficacy due to counterregulatory events. |
| Databáze: | OpenAIRE |
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