Paradoxical cAMP-induced lung endothelial hyperpermeability revealed by Pseudomonas aeruginosa ExoY. Circ Res 2004 Jul 23;95(2):196-203
Date
06/12/2004Pubmed ID
15192021DOI
10.1161/01.RES.0000134922.25721.d9Scopus ID
2-s2.0-3343017244 (requires institutional sign-in at Scopus site) 106 CitationsAbstract
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 (ExoY(K81M)) 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.
Author List
Sayner SL, Frank DW, King J, Chen H, VandeWaa J, Stevens TAuthor
Dara W. Frank PhD Professor in the Microbiology and Immunology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
3',5'-Cyclic-AMP PhosphodiesterasesAdenylyl Cyclase Inhibitors
Adenylyl Cyclases
Animals
Bacterial Proteins
Capillaries
Catalysis
Cell Compartmentation
Cell Membrane Permeability
Cells, Cultured
Colforsin
Cyclic AMP
Cyclic Nucleotide Phosphodiesterases, Type 4
Cytosol
Endothelial Cells
Endothelium, Vascular
Glucosyltransferases
Intercellular Junctions
Lung
Male
Phosphodiesterase Inhibitors
Pseudomonas aeruginosa
Rats
Rats, Sprague-Dawley
Rolipram
Second Messenger Systems
Structure-Activity Relationship
