期刊
CIRCULATION RESEARCH
卷 95, 期 2, 页码 196-203出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/01.RES.0000134922.25721.d9
关键词
adenylyl cyclase; phosphodiesterase; signal transduction; edema; Bacillus anthracis
资金
- NHLBI NIH HHS [HL-66299, HL59239, HL-60024] Funding Source: Medline
- NIAID NIH HHS [AI49577] Funding Source: Medline
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.
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