Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 289, Issue 33, Pages 23065-23074Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M114.557652
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Funding
- National Institutes of Health [HL58506, AG041265, HL087560, HL114471]
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Inhaled beta-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 beta-agonist treatment. This study aims to clarify the role of PKA in the prorelaxant effects of beta-agonists on ASM. Inhibition of PKA activity via expression of the PKI and RevAB peptides results in increased beta-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, beta-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 beta-agonists exert their relaxant effects.
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