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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