Published online before print February 9, 2006, doi: 10.1161/01.RES.0000209516.84815.3e
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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
Related Article:
- Is cAMP Good or Bad?: Depends on Where It’s Made
- Rodolphe Fischmeister
Circ. Res. 2006 98: 582-584.[Extract] [Full Text] [PDF]
This article has been cited by other articles:
 |
|
 |
|
  B. Ye, S. L. Kroboth, J.-L. Pu, J. J. Sims, N. T. Aggarwal, E. M. McNally, J. C. Makielski, and N.-Q. Shi Molecular Identification and Functional Characterization of a Mitochondrial Sulfonylurea Receptor 2 Splice Variant Generated by Intraexonic Splicing Circ. Res., November 20, 2009; 105(11): 1083 - 1093. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. W. Dessauer Adenylyl Cyclase-A-kinase Anchoring Protein Complexes: The Next Dimension in cAMP Signaling Mol. Pharmacol., November 1, 2009; 76(5): 935 - 941. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R.C. Werthmann, K. von Hayn, V.O. Nikolaev, M.J. Lohse, and M. Bünemann Real-time monitoring of cAMP levels in living endothelial cells: thrombin transiently inhibits adenylyl cyclase 6 J. Physiol., August 15, 2009; 587(16): 4091 - 4104. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Prasain, M. Alexeyev, R. Balczon, and T. Stevens Soluble adenylyl cyclase-dependent microtubule disassembly reveals a novel mechanism of endothelial cell retraction Am J Physiol Lung Cell Mol Physiol, July 1, 2009; 297(1): L73 - L83. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Kumar, S. Kostin, J.-P. Flacke, H. P. Reusch, and Y. Ladilov Soluble Adenylyl Cyclase Controls Mitochondria-dependent Apoptosis in Coronary Endothelial Cells J. Biol. Chem., May 29, 2009; 284(22): 14760 - 14768. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. A. Paulucci-Holthauzen, L. A. Vergara, L. J. Bellot, D. Canton, J. D. Scott, and K. L. O'Connor Spatial Distribution of Protein Kinase A Activity during Cell Migration Is Mediated by A-kinase Anchoring Protein AKAP Lbc J. Biol. Chem., February 27, 2009; 284(9): 5956 - 5967. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. M. Mutlu and P. Factor Alveolar Epithelial 2-Adrenergic Receptors Am. J. Respir. Cell Mol. Biol., February 1, 2008; 38(2): 127 - 134. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Creighton, B. Zhu, M. Alexeyev, and T. Stevens Spectrin-anchored phosphodiesterase 4D4 restricts cAMP from disrupting microtubules and inducing endothelial cell gap formation J. Cell Sci., January 1, 2008; 121(1): 110 - 119. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Surapisitchat, K.-I. Jeon, C. Yan, and J. A. Beavo Differential Regulation of Endothelial Cell Permeability by cGMP via Phosphodiesterases 2 and 3 Circ. Res., October 12, 2007; 101(8): 811 - 818. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. J. Netherton, J. A. Sutton, L. S. Wilson, R. L. Carter, and D. H. Maurice Both Protein Kinase A and Exchange Protein Activated by cAMP Coordinate Adhesion of Human Vascular Endothelial Cells Circ. Res., October 12, 2007; 101(8): 768 - 776. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Willoughby and D. M. F. Cooper Organization and Ca2+ Regulation of Adenylyl Cyclases in cAMP Microdomains Physiol Rev, July 1, 2007; 87(3): 965 - 1010. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Zaccolo and M. A. Movsesian cAMP and cGMP Signaling Cross-Talk: Role of Phosphodiesterases and Implications for Cardiac Pathophysiology Circ. Res., June 8, 2007; 100(11): 1569 - 1578. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Fischmeister Is cAMP Good or Bad?: Depends on Where It's Made Circ. Res., March 17, 2006; 98(5): 582 - 584. [Full Text] [PDF]
|
|