β 2-Adrenoceptor agonist-induced RGS2 expression is a genomic mechanism of bronchoprotection that is enhanced by glucocorticoids

Neil S. Holden, Matthew J. Bell, Christopher F. Rider, Elizabeth M. King, David D. Gaunt, Richard Leigh, Malcolm Johnson, David P. Siderovski, Scott P. Heximer, Mark A. Giembycz, Robert Newton

Research output: Contribution to journalArticle

56 Scopus citations

Abstract

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 β 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.

Original languageEnglish
Pages (from-to)19713-19718
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number49
DOIs
StatePublished - 6 Dec 2011

Keywords

  • Adrenoreceptor
  • Beta-2-adrenergic receptor
  • Glucocorticoid receptor
  • NR3C1
  • Protein kinase A

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