β‐Arrestins specifically constrain β2‐adrenergic receptor signaling and function in airway smooth muscle
Open Access
- 11 February 2008
- journal article
- research article
- Published by Wiley in The FASEB Journal
- Vol. 22 (7), 2134-2141
- https://doi.org/10.1096/fj.07-102459
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 E2 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.—Deshpande, D. A., Theriot, B. S., Penn, R. B., Walker, J. K. L. β‐Arrestins specifically constrain β2‐adrenergic receptor signaling and function in airway smooth muscle. FASEB J. 22, 2134–2141 (2008)Keywords
Funding Information
- Reckitt Benckiser Pharmaceuticals (HL-58506, AI059755)
- U.S. Department of Veterans Affairs (HL-084123)
- Claude Pepper Older Americans Independence Center, Wake Forest School of Medicine (K99 HL-087560)
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