期刊
FASEB JOURNAL
卷 22, 期 7, 页码 2134-2141出版社
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.07-102459
关键词
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资金
- NHLBI NIH HHS [R29 HL058506, R01 HL058506, HL-084123, K99 HL087560, HL-58506, K99 HL-087560, R01 HL084123, R01 HL093103] Funding Source: Medline
- NIAID NIH HHS [AI059755, R01 AI059755] Funding Source: Medline
Chronic use of inhaled beta-agonists by asthmatics is associated with a loss of bronchoprotective effect and deterioration of asthma control. Beta-agonistpromoted desensitization of airway smooth muscle beta-2-adrenergic receptors, mediated by G protein-coupled receptor kinases and arrestins, is presumed to underlie these effects, but such a mechanism has never been demonstrated. Using in vitro, ex vivo, and in vivo murine models, we demonstrate that beta-arrestin-2 gene ablation augments beta-agonist-mediated airway smooth muscle relaxation, while augmenting beta-agonist-stimulated cyclic adenosine monophosphate production. In cultures of human airway smooth muscle, small interfering RNA-mediated knockdown of arrestins also augments beta-agonist-stimulated cyclic adenosine monophosphate production. Interestingly, signaling and function mediated by m2/m3 muscarinic acetylcholine receptors or prostaglandin E-2 receptors were not affected by either beta-arrestin-2 knockout or arrestin knockdown. Thus, arrestins are selective regulators of beta-2-adrenergic receptor signaling and function in airway smooth muscle. These results and our previous findings, which demonstrate a role for arrestins in the development of allergic inflammation in the lung, identify arrestins as potentially important therapeutic targets for obstructive airway diseases.
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