PubAg

Main content area

β2-Adrenoceptor agonist-induced RGS2 expression is a genomic mechanism of bronchoprotection that is enhanced by glucocorticoids

Author:
Holden, Neil S., Bell, Matthew J., Rider, Christopher F., King, Elizabeth M., Gaunt, David D., Leigh, Richard, Johnson, Malcolm, Siderovski, David P., Heximer, Scott P., Giembycz, Mark A., Newton, Robert
Source:
Proceedings of the National Academy of Sciences of the United States of America 2011 v.108 no.49 pp. 19713-19718
ISSN:
0027-8424
Subject:
G-proteins, GTPase-activating proteins, agonists, asthma, bronchoconstriction, calcium, gene expression, genomics, glucocorticoids, histamine, humans, leukotrienes, mice, myocytes, receptors, smooth muscle
Abstract:
In asthma and chronic obstructive pulmonary disease, activation of Gq-protein–coupled receptors causes bronchoconstriction. In each case, the management of moderate-to-severe disease uses inhaled corticosteroid (glucocorticoid)/long-acting β2-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 Gq 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.
Agid:
190793