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FASEB J. 2008 Jul;22(7):2134-41. doi: 10.1096/fj.07-102459. Epub 2008 Mar 12.

Beta-arrestins specifically constrain beta2-adrenergic receptor signaling and function in airway smooth muscle.

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  • 1Department of Internal Medicine and Center for Human Genomics, Wake Forest University Health Sciences, Winston-Salem, North Carolina 27157, USA.

Abstract

Chronic use of inhaled beta-agonists by asthmatics is associated with a loss of bronchoprotective effect and deterioration of asthma control. Beta-agonist-promoted 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.

PMID:
18337459
[PubMed - indexed for MEDLINE]
PMCID:
PMC3514410
Free PMC Article
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