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Epac as a novel relaxant factor in airway smooth muscle
Author(s) -
Schmidt Martina,
Roscioni Sara,
Maarsingh Harm,
Meurs Herman,
Halayko Andrew
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.970.2
Subject(s) - contraction (grammar) , myosin light chain kinase , airway , rac1 , chemistry , microbiology and biotechnology , stress fiber , phosphorylation , myosin , muscle contraction , anatomy , endocrinology , biology , medicine , anesthesia , signal transduction , focal adhesion
Obstructive airway diseases are characterized by airway narrowing and progressive lung function decline. Elevations of cAMP by β 2 ‐adrenoceptors reverse airway smooth muscle contraction, a process classically assigned to protein kinase A (PKA). Here we report on a novel cAMP mechanism which regulates airway smooth muscle relaxation. Specific activation of Epac (exchange protein directly activated by cAMP) relaxes pre‐contracted guinea pig tracheal open‐rings independent of PKA. Importantly, human airway smooth muscle also expresses Epac and activated Epac relaxes pre‐contracted human airway smooth muscle. Contraction of smooth muscle cells is believed to depend on Rho/Rac balancing. Regulation of cytoskeleton dynamics by Rho increases myosin light chain (MLC) phosphorylation and stress fiber formation, whereas activation of Rac has the opposite effect. Toxin B‐1470‐inhibited Rac1 attenuated in guinea pig tracheal rings Epac‐mediated airway smooth muscle relaxation, suggesting a key role for Rac1 in the relaxing properties of Epac. Indeed, activation of Epac induced GTP‐loading Rac1 and minimized metacholine‐induced stress fiber formation and MCL phosphorylation in airway smooth muscle. We identify Epac as a novel relaxing factor in airway smooth muscle, most likely by shifting the Rho/Rac balance towards Rac1. Therefore, activation of Epac may have therapeutical potential in the treatment of obstructive airway diseases.