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Publication Detail

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

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

Published In J Biol Chem, (2014 Aug 15)

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.

PubMed ID: 24973219 Exiting the NIEHS site

MeSH Terms: 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*

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