RGS5 Archives - World Asthma Foundation

RGS5 gene and therapeutic response to short acting bronchodilators in paediatric asthma patients.

Pediatr Pulmonol. 2012 Nov 28;

Authors: Labuda M, Laberge S, Brière J, Bérubé D, Krajinovic M

Abstract
Short-acting ?2-adrenergic receptor agonists are commonly used bronchodilators for symptom relief in asthmatics. Recent evidence demonstrated that prolonged exposure of cultured airway smooth muscle cells to ?2 agonists directly augments procontractile signaling pathways with the change in expression of regulator of G protein signaling 5 (RGS5). The aim of this study was to test whether genetic variants in RGS5 gene affect the response to short acting ?2-agonists. Bronchodilator responsiveness was assessed in 137 asthmatic children by % change in baseline forced expiratory volume in 1?sec (FEV(1) ) after administration of albuterol. The analyses were performed in patients with FEV(1) /FVC ratio below 0.9 (FVC-forced vital capacity, n?=?99). FEV(1) % change adjusted for baseline FEV(1) values was significantly different between genotypes of rs10917696 C/T polymorphism (P?=?0.008). The association remained significant with inclusion of age, sex, atopy, parental smoking, and controller medications into multivariate model (P?=?0.005). We also identified additive effect on the treatment outcome with previously published genetic variant G/A rs1544791 in phosphodiesterase 4 (PDE4D) gene. Carriers of two risk alleles (C and G) had adjusted mean % FEV(1) change value 4.6?±?1.3, while carriers of one and none of the risk alleles had 8.1?±?0.7% and 13.5?±?2.4%, respectively, P?=?0.001. Our work identifies a new genetic variant in RGS5 demonstrating additive effect with PDE4D, both implicated in modulation of asthma treatment. Pediatr Pulmonol. © 2012 Wiley Periodicals, Inc.

PMID: 23193110 [PubMed – as supplied by publisher]

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RGS5 Inhibits Bronchial Smooth Muscle Contraction in Severe Asthma.

Am J Respir Cell Mol Biol. 2012 Jan 26;

Authors: Yang Z, Balenga N, Cooper PR, Damera G, Edwards R, Brightling CE, Panettieri Jr RA, Druey KM

Abstract
Severe asthma is associated with fixed airway obstruction due to inflammation, copious luminal mucous, and increased airway smooth muscle (ASM) mass. Paradoxically, studies have demonstrated that hypertrophic and hyperplastic ASM characteristic of severe asthma has reduced contractile capacity. We compared GPCR-induced Ca(2+) mobilization and expression of GPCRs and signaling proteins related to procontractile signaling in ASM derived post-mortem from subjects who died of non-respiratory causes to cells from subjects who died of asthma. Despite increased or comparable expression of contraction-promoting GPCRs (bradykinin B2 or histamine H1 and PAR1, respectively) in asthmatic ASM cells relative to cells from healthy donors, asthmatic ASM cells had reduced histamine-induced Ca(2+) mobilization and comparable responses to bradykinin and thrombin, suggesting a post-receptor signaling defect. Accordingly, expression of Regulator of G protein signaling 5 (RGS5), an inhibitor of ASM contraction, was increased in cultured asthmatic ASM cells and in bronchial smooth muscle bundles of both asthmatic human subjects and allergen-challenged mice relative to those of healthy human subjects or naïve mice. Overexpression of RGS5 impaired Ca(2+)release to thrombin, histamine and carbachol and reduced contraction of precision-cut lung slices (PCLS) to carbachol. These results suggest that increased RGS5 expression contributes to decreased myocyte shortening in severe and/or fatal asthma.

PMID: 22281988 [PubMed – as supplied by publisher]

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