-Agonist-associated Reduction in RGS5 Expression Promotes Airway Smooth Muscle Hyper-responsiveness

Molecular Signal Transduction Section, Laboratory of Allergic Diseases, NIAID, National Institutes of Health, Bethesda, Maryland 20892, USA.
Journal of Biological Chemistry (Impact Factor: 4.57). 04/2011; 286(13):11444-55. DOI: 10.1074/jbc.M110.212480
Source: PubMed


Although short-acting and long-acting inhaled β2-adrenergic receptor agonists (SABA and LABA, respectively) relieve asthma symptoms, use of either agent alone without concomitant
anti-inflammatory drugs (corticosteroids) may increase the risk of disease exacerbation in some patients. We found previously
that pretreatment of human precision-cut lung slices (PCLS) with SABA impaired subsequent β2-agonist-induced bronchodilation, which occurred independently of changes in receptor quantities. Here we provide evidence
that prolonged exposure of cultured human airway smooth muscle (HuASM) cells to β2-agonists directly augments procontractile signaling pathways elicited by several compounds including thrombin, bradykinin,
and histamine. Such treatment did not increase surface receptor amounts or expression of G proteins and downstream effectors
(phospholipase Cβ and myosin light chain). In contrast, β-agonists decreased expression of regulator of G protein signaling
5 (RGS5), which is an inhibitor of G-protein-coupled receptor (GPCR) activity. RGS5 knockdown in HuASM increased agonist-evoked
intracellular calcium flux and myosin light chain (MLC) phosphorylation, which are prerequisites for contraction. PCLS from
Rgs5−/− mice contracted more to carbachol than those from WT mice, indicating that RGS5 negatively regulates bronchial smooth muscle
contraction. Repetitive β2-agonist use may not only lead to reduced bronchoprotection but also to sensitization of excitation-contraction signaling
pathways as a result of reduced RGS5 expression.

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