β-agonist-mediated relaxation of airway smooth muscle is protein kinase A-dependent

Sarah J. Morgan, Deepak A. Deshpande, Brian C. Tiegs, Anna M. Misior, Huandong Yan, Alena V. Hershfeld, Thomas C. Rich, Reynold A. Panettieri, Steven S. An, Raymond B. Penn

Research output: Contribution to journalArticle

Abstract

Inhaled β-agonists are effective at reversing bronchoconstriction in asthma, but the mechanism by which they exert this effect is unclear and controversial. PKA is the historically accepted effector, although this assumption is made on the basis of associative and not direct evidence. Recent studies have asserted that exchange protein activated by cAMP (Epac), not PKA, mediates the relaxation of airway smooth muscle (ASM) observed with β-agonist treatment. This study aims to clarify the role of PKA in the prorelaxant effects of β-agonists on ASM. Inhibition of PKA activity via expression of the PKI and RevAB peptides results in increased β-agonist-mediated cAMP release, abolishes the inhibitory effect of isoproterenol on histamine-induced intracellular calcium flux, and significantly attenuates histamine-stimulated MLC-20 phosphorylation. Analyses of ASM cell and tissue contraction demonstrate that PKA inhibition eliminates most, if not all, β-agonist-mediated relaxation of contracted smooth muscle. Conversely, Epac knockdown had no effect on the regulation of contraction or procontractile signaling by isoproterenol. These findings suggest that PKA, not Epac, is the predominant and physiologically relevant effector through which β-agonists exert their relaxant effects.

Original languageEnglish (US)
Pages (from-to)23065-23074
Number of pages10
JournalJournal of Biological Chemistry
Volume289
Issue number33
DOIs
StatePublished - Aug 15 2014

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Morgan, S. J., Deshpande, D. A., Tiegs, B. C., Misior, A. M., Yan, H., Hershfeld, A. V., Rich, T. C., Panettieri, R. A., An, S. S., & Penn, R. B. (2014). β-agonist-mediated relaxation of airway smooth muscle is protein kinase A-dependent. Journal of Biological Chemistry, 289(33), 23065-23074. https://doi.org/10.1074/jbc.M114.557652