Mechanisms of acute desensitization of the β2AR-adenylyl cyclase pathway in human airway smooth muscle

Raymond B. Penn, Reynold A. Panettieri, Jeffrey L. Benovic

Research output: Contribution to journalArticlepeer-review

83 Scopus citations


β2-Adrenergic receptors (β2ARs) are important regulators of airway smooth muscle tone, and β-sympathomimetic drugs are the most widely used agents in asthma therapy and are universally recognized as the treatment of choice for acute asthma attacks. Despite the clinical importance of β-agonists and a good understanding of their mechanism of action in airway smooth muscle relaxation, surprisingly little is known about the manner in which the β2AR signaling pathway is regulated in human airway smooth muscle (HASM). In this communication, we characterize mechanisms underlying rapid desensitization of the HASM β2AR-adenylyl cyclase (AC) pathway. Acute homologous desensitization of β2AR-mediated cyclic adenosine monophosphate (cAMP) production was characterized by an ∼ 60% loss of maximal responsiveness to isoproterenol (ISO) when cells were pretreated for 30 min with 1 μM ISO. Acute heterologous β2AR desensitization was characterized by an ∼ 20% and 30% loss of maximal responsiveness to ISO challenge when cells were pretreated with forskolin and prostaglandin E2 (PGE2), respectively. Each form of desensitization was also characterized by an increase in the EC50 for ISO. β2AR sequestration was associated with but not required for homologous desensitization. However, sequestration was required for rapid resensitization. Minimal alterations in inherent AC activity were observed with both modes of desensitization, suggesting that the β2AR is the principal locus of regulation. Protein kinase inhibition by staurosporine largely reversed heterologous β2AR desensitization and had a small but significant effect on homologous desensitization. In contrast, bisindolylmaleimide IX, a specific PKC-inhibitor, had no effect on heterologous or homologous β2AR desensitization, suggesting that staurosporine effects were mediated by PKA inhibition. Overexpression of the G protein-coupled receptor kinase GRK2 in HASM cultures enhanced homologous desensitization. These data suggest that HASM β2ARs are highly susceptible to rapid desensitization by multiple agents, and identify both GRKs and PKA as important mediators of acute β2AR desensitization.

Original languageEnglish (US)
Pages (from-to)338-348
Number of pages11
JournalAmerican journal of respiratory cell and molecular biology
Issue number2
StatePublished - 1998

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

Fingerprint Dive into the research topics of 'Mechanisms of acute desensitization of the β<sub>2</sub>AR-adenylyl cyclase pathway in human airway smooth muscle'. Together they form a unique fingerprint.

Cite this