Published online before print February 9, 2006, doi: 10.1161/01.RES.0000209516.84815.3e
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Submitted on September 13, 2005
Revised on January 19, 2006
Accepted on January 26, 2006
Soluble Adenylyl Cyclase Reveals the Significance of cAMP Compartmentation on Pulmonary Microvascular Endothelial Cell Barrier
Sarah L. Sayner ;
From the Center for Lung Biology (S.S., M.A., T.S.) and Departments of Pharmacology (S.S., T.S.), Cell Biology (M.A.), and Neuroscience (M.A.), University of South Alabama College of Medicine, Mobile; and Integrative Biology and Pharmacology (C.W.D.), University of Texas, Houston.
* To whom correspondence should be addressed. E-mail: tstevens{at}jaguar1.usouthal.edu.
Subtle elevations in cAMP localized to the plasma membrane intensely strengthen endothelial barrier function. Paradoxically, pathogenic bacteria insert adenylyl cyclases (ACs) into eukaryotic cells generating a time-dependent cytosolic cAMP-increase that disrupts rather than strengthens the endothelial barrier. These findings bring into question whether membrane versus cytosolic AC activity dominates in control of cell adhesion. To address this problem, a mammalian forskolin-sensitive soluble AC (sACI/II) was expressed in pulmonary microvascular endothelial cells. Forskolin stimulated this sACI/II construct generating a small cytosolic cAMP-pool that was not regulated by phosphodiesterases or G
s. Whereas forskolin simultaneously activated the sACI/II construct and endogenous transmembrane ACs, the modest sACI/II activity overwhelmed the barrier protective effects of plasma membrane activity to induce endothelial gap formation. Retargeting sACI/II to the plasma membrane retained AC activity but protected the endothelial cell barrier. These findings demonstrate for the first time that the intracellular location of cAMP synthesis critically determines its physiological outcome.
Key words: phosphodiesterase • signal transduction • ExoY • second messenger • Pseudomonas aeruginosa
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