Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 108, Issue 49, Pages 19713-19718Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1110226108
Keywords
adrenoreceptor; beta-2-adrenergic receptor; protein kinase A; glucocorticoid receptor; NR3C1
Categories
Funding
- Canadian Institutes of Health Research
- GlaxoSmithKline, United Kingdom
- Lung Association of Alberta and North West Territories
- Alberta Innovates-Health Solutions
- Izaak Walton Killam Post-Doctoral Fellowship
- Canadian Fund for Innovation
- GlaxoSmithKline
- GlaxoSmithKline Canada
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In asthma and chronic obstructive pulmonary disease, activation of G(q)-protein-coupled receptors causes bronchoconstriction. In each case, the management of moderate-to-severe disease uses inhaled corticosteroid (glucocorticoid)/long-acting beta(2)-adrenoceptor agonist (LABA) combination therapies, which are more efficacious than either monotherapy alone. In primary human airway smooth muscle cells, glucocorticoid/LABA combinations synergistically induce the expression of regulator of G-protein signaling 2 (RGS2), a GTPase-activating protein that attenuates G(q) signaling. Functionally, RGS2 reduced intracellular free calcium flux elicited by histamine, methacholine, leukotrienes, and other spasmogens. Furthermore, protection against spasmogen-increased intracellular free calcium, following treatment for 6 h with LABA plus corticosteroid, was dependent on RGS2. Finally, Rgs2-deficient mice revealed enhanced bronchoconstriction to spasmogens and an absence of LABA-induced bronchoprotection. These data identify RGS2 gene expression as a genomic mechanism of bronchoprotection that is induced by glucocorticoids plus LABAs in human airway smooth muscle and provide a rational explanation for the clinical efficacy of inhaled corticosteroid (glucocorticoid)/LABA combinations in obstructive airways diseases.
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