Glucocorticoids rapidly activate cAMP production via Gαsto initiate non‐genomic signaling that contributes to one‐third of their canonical genomic effects
| Autor: | Austin G. Kazarian, Maia L. Corpuz, Rennolds S. Ostrom, Cynthia J. Koziol-White, Francisco J. Nuñez, Moom R. Roosan, Timothy B. Johnstone, Nicole N. Mohajer, Reynold A. Panettieri, Omar Tliba |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Cell signaling Gs alpha subunit G protein Phosphodiesterase Biochemistry 3. Good health Cell biology 03 medical and health sciences chemistry.chemical_compound 030104 developmental biology 0302 clinical medicine chemistry Genetics medicine Cyclic adenosine monophosphate Receptor Molecular Biology 030217 neurology & neurosurgery Glucocorticoid Biotechnology G protein-coupled receptor medicine.drug |
| Zdroj: | The FASEB Journal. 34:2882-2895 |
| ISSN: | 1530-6860 0892-6638 |
| Popis: | Glucocorticoids are widely used for the suppression of inflammation, but evidence is growing that they can have rapid, non-genomic actions that have been unappreciated. Diverse cell signaling effects have been reported for glucocorticoids, leading us to hypothesize that glucocorticoids alone can swiftly increase the 3',5'-cyclic adenosine monophosphate (cAMP) production. We found that prednisone, fluticasone, budesonide, and progesterone each increased cAMP levels within 3 minutes without phosphodiesterase inhibitors by measuring real-time cAMP dynamics using the cAMP difference detector in situ assay in a variety of immortalized cell lines and primary human airway smooth muscle (HASM) cells. A membrane- impermeable glucocorticoid showed similarly rapid stimulation of cAMP, implying that responses are initiated at the cell surface. siRNA knockdown of Gαs virtually eliminated glucocorticoid-stimulated cAMP responses, suggesting that these drugs activate the cAMP production via a G protein-coupled receptor. Estradiol had small effects on cAMP levels but G protein estrogen receptor antagonists had little effect on responses to any of the glucocorticoids tested. The genomic and non-genomic actions of budesonide were analyzed by RNA-Seq analysis of 24 hours treated HASM, with and without knockdown of Gαs . A 140-gene budesonide signature was identified, of which 48 genes represent a non-genomic signature that requires Gαs signaling. Collectively, this non-genomic cAMP signaling modality contributes to one-third of the gene expression changes induced by glucocorticoid treatment and shifts the view of how this important class of drugs exerts its effects. |
| Databáze: | OpenAIRE |
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