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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Arrestins / deficiency
  • Arrestins / genetics
  • Arrestins / physiology*
  • Cell Membrane / physiology
  • Inflammation / physiopathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Muscle Contraction
  • Muscle, Smooth / physiology
  • Muscle, Smooth / physiopathology
  • Receptors, Adrenergic, beta-2 / physiology*
  • Respiratory Function Tests
  • Respiratory Muscles / physiology*
  • Respiratory Muscles / physiopathology
  • Signal Transduction
  • Stress, Mechanical
  • Trachea / physiology
  • beta-Arrestin 2
  • beta-Arrestins

Substances

  • ARRB2 protein, human
  • Arrb2 protein, mouse
  • Arrestins
  • Receptors, Adrenergic, beta-2
  • beta-Arrestin 2
  • beta-Arrestins