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

Holden, Neil S. and Bell, Matthew J. and Rider, Christopher F. and King, Elizabeth M. and Gaunt, David D. and Leigh, Richard and Johnson, Malcolm and Siderovski, David P. and Heximer, Scott P. and Giembycz, Mark A. and Newton, Robert (2011) β2-Adrenoceptor agonist-induced RGS2 expression is a genomic mechanism of bronchoprotection that is enhanced by glucocorticoids. Proceedings of the National Academy of Sciences of the United States of America, 108 (49). pp. 19713-19718. ISSN 1091-6490

Full content URL: http://www.pnas.org/content/108/49/19713

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

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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.

Keywords:Adrenoreceptor, beta-2-adrenergic receptor, protein kinase A, glucocorticoid receptor, NR3C1
Subjects:C Biological Sciences > C190 Biology not elsewhere classified
A Medicine and Dentistry > A990 Medicine and Dentistry not elsewhere classified
Divisions:College of Science > School of Life Sciences
ID Code:15116
Deposited On:22 Oct 2014 11:19

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