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Am J Physiol Lung Cell Mol Physiol 297: L746-L757, 2009. First published August 7, 2009; doi:10.1152/ajplung.00079.2009
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Mechanism regulating proasthmatic effects of prolonged homologous β2-adrenergic receptor desensitization in airway smooth muscle

Gustavo Nino, Aihua Hu, Judith S. Grunstein, and Michael M. Grunstein

The Joseph Stokes Jr. Research Institute, Division of Pulmonary Medicine, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania

Submitted 9 March 2009 ; accepted in final form 4 August 2009

Use of long-acting β2-adrenergic receptor (β2AR) agonists to treat asthma incurs an increased risk of asthma morbidity with impaired bronchodilation and heightened bronchoconstriction, reflecting the adverse effects of prolonged homologous β2AR desensitization on airway smooth muscle (ASM) function. Since phosphodiesterase 4 (PDE4) regulates ASM relaxation and contractility, we examined whether the changes in ASM function induced by prolonged homologous β2AR desensitization are attributed to altered expression and action of PDE4. Cultured human ASM cells and isolated rabbit ASM tissues exposed for 24 h to the long-acting β2AR agonist salmeterol exhibited impaired acute β2AR-mediated cAMP accumulation and relaxation, respectively, together with ASM constrictor hyperresponsiveness. These proasthmatic-like changes in ASM function were associated with upregulated PDE4 activity due to enhanced expression of the PDE4D5 isoform and were prevented by pretreating the ASM preparations with the PDE4 inhibitor rolipram or with inhibitors of either PKA or ERK1/2 signaling. Extended studies using gene silencing and pharmacological approaches demonstrated that: 1) the mechanism underlying upregulated PDE4D5 expression following prolonged β2AR agonist exposure involves PKA-dependent activation of Gi protein signaling via its β{gamma}-subunits, which elicits downstream activation of ERK1/2 and its induction of PDE4D5 transcription; and 2) the induction of PDE4 activity and consequent changes in ASM responsiveness are prevented by pretreating the β2AR agonist-exposed ASM preparations with inhibitors of Gi-β{gamma} signaling. Collectively, these findings identify that the proasthmatic changes in ASM function resulting from prolonged homologous β2AR desensitization are attributed to upregulated PDE4 expression induced by Gi-β{gamma}-mediated cross-talk between the PKA and ERK1/2 signaling pathways.

asthma; long-acting β2-agonists; salmeterol; cAMP signaling; G proteins; phosphodiesterase-4


Address for reprint requests and other correspondence: M. M. Grunstein, Division of Pulmonary Medicine, Abramson Research Bldg., Children's Hospital of Philadelphia, 34th St. and Civic Center Blvd., Philadelphia, PA 19104 (e-mail: grunstein{at}email.chop.edu).






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