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J Biol Chem. 2014 Aug 15;289(33):23065-74. doi: 10.1074/jbc.M114.557652. Epub 2014 Jun 27.

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

Author information

1
From the Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of Maryland School of Medicine, Baltimore, Maryland 21201.
2
the Department of Internal Medicine, Wake Forest University Health Sciences, Winston-Salem, North Carolina 27106.
3
the Department of Pharmacology, College of Medicine and Center for Lung Biology, University of South Alabama, Mobile, Alabama 36688.
4
the Department of Medicine, Pulmonary, Allergy, and Critical Care Division, Airways Biology Initiative, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104.
5
the Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 21205, and.
6
From the Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of Maryland School of Medicine, Baltimore, Maryland 21201, the Department of Medicine, Division of Pulmonary and Critical Care Medicine, Center for Translational Medicine, Jane and Leonard Korman Lung Center, Thomas Jefferson University, Philadelphia, Pennsylvania 19107 Raymond.Penn@jefferson.edu.

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.

KEYWORDS:

Adrenergic Receptor; Asthma; G Protein-coupled Receptor (GPCR); Protein Kinase A (PKA); Smooth Muscle

PMID:
24973219
PMCID:
PMC4132805
DOI:
10.1074/jbc.M114.557652
[Indexed for MEDLINE]
Free PMC Article
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