title: β2-Adrenoceptor agonist-induced RGS2 expression is a genomic mechanism of bronchoprotection that is enhanced by glucocorticoids.
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.
authors.affiliation: Airways Inflammation Research Group, Faculty of Medicine,  University of Calgary, Calgary, AB,  Canada T2N 4N1.
authors.forename: Neil S
authors.initials: NS
authors.lastname: Holden
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Bell
authors.forename: Christopher F
authors.initials: CF
authors.lastname: Rider
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: King
authors.forename: David D
authors.initials: DD
authors.lastname: Gaunt
authors.forename: Richard
authors.initials: R
authors.lastname: Leigh
authors.forename: Malcolm
authors.initials: M
authors.lastname: Johnson
authors.forename: David P
authors.initials: DP
authors.lastname: Siderovski
authors.forename: Scott P
authors.initials: SP
authors.lastname: Heximer
authors.forename: Mark A
authors.initials: MA
authors.lastname: Giembycz
authors.forename: Robert
authors.initials: R
authors.lastname: Newton
mesh_terms: D058666:Adrenergic beta-2 Receptor Agonists / Q000494:pharmacology*; D000420:Albuterol / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D016084:Bronchoconstriction / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D019819:Budesonide / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology; D004357:Drug Synergism; D004983:Ethanolamines / Q000494:pharmacology; D000068759:Formoterol Fumarate; D015870:Gene Expression / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D008168:Lung / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009130:Muscle, Smooth / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D020710:RGS Proteins / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000068299:Salmeterol Xinafoate
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D004983:Ethanolamines; D005938:Glucocorticoids; D020710:RGS Proteins; C087182:RGS2 protein, human; C105345:Rgs2 protein, mouse; D019819:Budesonide; D000068299:Salmeterol Xinafoate; D003907:Dexamethasone; D000420:Albuterol; D002118:Calcium; D000068759:Formoterol Fumarate
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