title: Beta-agonist-associated reduction in RGS5 expression promotes airway smooth muscle hyper-responsiveness.
abstract: Although short-acting and long-acting inhaled β(2)-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 β(2)-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 β(2)-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 β(2)-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.
authors.affiliation: Molecular Signal Transduction Section, Laboratory of Allergic Diseases, NIAID, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Zhao
authors.initials: Z
authors.lastname: Yang
authors.forename: Philip R
authors.initials: PR
authors.lastname: Cooper
authors.forename: Gautam
authors.initials: G
authors.lastname: Damera
authors.forename: Indranil
authors.initials: I
authors.lastname: Mukhopadhyay
authors.forename: Hyeseon
authors.initials: H
authors.lastname: Cho
authors.forename: John H
authors.initials: JH
authors.lastname: Kehrl
authors.forename: Reynold A
authors.initials: RA
authors.lastname: Panettieri
authors.forename: Kirk M
authors.initials: KM
authors.lastname: Druey
mesh_terms: D058666:Adrenergic beta-2 Receptor Agonists / Q000494:pharmacology*; D000818:Animals; D005786:Gene Expression Regulation / Q000187:drug effects*; D057809:HEK293 Cells; D006801:Humans; D008168:Lung / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D018994:Myosin Light Chains / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D020710:RGS Proteins / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D018994:Myosin Light Chains; D020710:RGS Proteins; C491349:RGS5 protein, human; C105346:Rgs5 protein, mouse