Beta-arrestins specifically constrain beta2-adrenergic receptor signaling and function in airway smooth muscle.
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.
Deshpande
Deepak A
DA
Department of Internal Medicine and Center for Human Genomics, Wake Forest University Health Sciences, Winston-Salem, North Carolina 27157, USA.
Theriot
Barbara S
BS
Penn
Raymond B
RB
Walker
Julia K L
JK
D000818:Animals; D019390:Arrestins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D002462:Cell Membrane / Q000502:physiology; D007249:Inflammation / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009119:Muscle Contraction; D009130:Muscle, Smooth / Q000502:physiology / Q000503:physiopathology; D018343:Receptors, Adrenergic, beta-2 / Q000502:physiology*; D012129:Respiratory Function Tests; D012132:Respiratory Muscles / Q000502:physiology* / Q000503:physiopathology; D015398:Signal Transduction; D013314:Stress, Mechanical; D014132:Trachea / Q000502:physiology; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins
C000605254:ARRB2 protein, human; C000605258:Arrb2 protein, mouse; D019390:Arrestins; D018343:Receptors, Adrenergic, beta-2; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins