Published online before print June 10, 2004, doi: 10.1161/01.RES.0000134922.25721.d9
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Submitted on January 8, 2004
Revised on May 21, 2004
Accepted on May 27, 2004
Paradoxical cAMP-Induced Lung Endothelial Hyperpermeability Revealed by Pseudomonas aeruginosa ExoY
Sarah L. Sayner ;
From the Center for Lung Biology (S.L.S., J.K., H.C., J.V.W., T.S.) and the Departments of Pharmacology (S.L.S., H.C., T.S.), Pathology (J.K.), and Medicine (J.V.W.), University of South Alabama College of Medicine, Mobile, Ala; and the Department of Microbiology and Molecular Genetics (D.W.F.), Medical College of Wisconsin, Milwaukee, Wis.
* To whom correspondence should be addressed. E-mail: tstevens{at}jaguar1.usouthal.edu.
Mammalian transmembrane adenylyl cyclases synthesize a restricted plasmalemmal cAMP pool that is intensely endothelial barrier protective. Bacteria have devised mechanisms of transferring eukaryotic factor-dependent adenylyl cyclases into mammalian cells. Pseudomonas aeruginosa ExoY is one such enzyme that catalyzes cytosolic cAMP synthesis, with unknown function. Pseudomonas aeruginosa genetically modified to introduce only the ExoY toxin elevated cAMP 800-fold in pulmonary microvascular endothelial cells over 4 hours, whereas a catalytically deficient (ExoYK81M) strain did not increase cAMP. ExoY-derived cAMP was localized to a cytosolic microdomain not regulated by phosphodiesterase activity. In contrast to the barrier-enhancing actions of plasmalemmal cAMP, the ExoY cytosolic cAMP pool induced endothelial gap formation and increased the filtration coefficient in the isolated perfused lung. These findings collectively illustrate a previously unrecognized mechanism of hyperpermeability induced by rises in cytosolic cAMP.
Key words: adenylyl cyclase • phosphodiesterase • signal transduction • edema • Bacillus anthracis
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