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

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
Proceedings of the National Academy of Sciences of the United States of America 2011 v.108 no.49 pp. 19713-19718
G-proteins, GTPase-activating proteins, agonists, asthma, bronchoconstriction, calcium, gene expression, genomics, glucocorticoids, histamine, humans, leukotrienes, mice, myocytes, receptors, smooth muscle
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.