β-Agonist-mediated Relaxation of Airway Smooth Muscle Is Protein Kinase A-dependent

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...

Full description

Saved in:
Bibliographic Details
Published in:The Journal of biological chemistry 2014-08, Vol.289 (33), p.23065-23074
Main Authors: Morgan, Sarah J., Deshpande, Deepak A., Tiegs, Brian C., Misior, Anna M., Yan, Huandong, Hershfeld, Alena V., Rich, Thomas C., Panettieri, Reynold A., An, Steven S., Penn, Raymond B.
Format: Article
Language:English
Subjects:
Adrenergic beta-Agonists - pharmacology
Cell Line
Cyclic AMP-Dependent Protein Kinases - metabolism
Guanine Nucleotide Exchange Factors - metabolism
Humans
Isoproterenol - pharmacology
Muscle Relaxation - drug effects
Muscle, Smooth - cytology
Muscle, Smooth - metabolism
Respiratory System - cytology
Respiratory System - metabolism
Signal Transduction
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M114.557652